Zinc salt compositions for the prevention of dermal and mucosal irritation

ABSTRACT

The present invention provides for compositions and methods that may offer protection from irritants as well as antimicrobial protection. Preferred embodiments of the invention include topical antimicrobial compositions that lack conventional antibiotics or preservatives, wherein the antimicrobial benefit is created by essential oils (or their active ingredients), emollient solvents and, in some instances, anti-inflammatory agents.

CROSS REFERENCE TO RELATED APPLICATIONS

The present invention is a continuation-in-part of U.S. patentapplication Ser. No. 10/622,272 filed Jul. 17, 2003, which is acontinuation-in-part of pending International Patent ApplicationPCT/US03/03896 filed Feb. 7, 2003, published in English as WO03/066001on Aug. 14, 2003, which claimed priority to provisional U.S. PatentApplication Ser. No. 60/355,549 filed Feb. 7, 2002, the contents ofwhich are incorporated herein by reference in their entireties.

1. INTRODUCTION

The present invention relates to methods and compositions which employlow concentrations of combinations of zinc salts to prevent theirritation of skin or mucous membranes that may be caused by therapeuticagents, by personal hygiene products, or by various physical, chemical,mechanical, or biological irritants, including infectious agents.

2. BACKGROUND OF THE INVENTION

The Center for Disease Control (CDC) estimates that hospital-acquiredinfections cost the U.S. healthcare system $4.5 billion a year, and that80% of these infections are transmitted by direct touch. Although thesimple use of soap before and after direct contact with a patient canreduce the transmission of these infections, health care workers oftenfail to employ this simple measure for several reasons. First, washingwith soap and water takes time. Second, such washing necessitates theuse of running water, sinks, paper towels and other infrastructuralneeds that are expensive to provide and maintain and therefore notalways immediately accessible by health-care personnel. Thus, mosthealth care workers follow the existing washing guidelines only about50% of the time.

In response to this problem, the CDC recently issued new hand hygieneguidelines for health care workers. One recommendation is for doctors,nurses and other health care workers to use alcohol-based handantiseptics rather than traditional water-based soaps to decontaminatetheir hands between contact with each patient to prevent the spread ofinfections. This new CDC guideline is expected to reduce the time spentto decontaminate hands and hence increase compliance among health-careworkers. Moreover, the recommended alcohol-based products can be carriedwith the health care worker or installed in several convenient placesnear patient rooms. The alcohol in the lotion will kill the bacteria,and added emollients should keep the hands soft. Furthermore, theproduct dries on the hands, so running water, sinks, paper towels, etc.are largely unnecessary.

A product called Avagard™, made by 3M, is commercially available havinga combination of emulsifiers, namely Beheneth-10, behenyl alcohol,cetylpalmitate, and diisopropyl dimer dilinoleate with 1% chlorhexidinegluconate solution and 61% ethyl alcohol (w/w).

A product called Prevacare™, made by Johnson & Johnson, is commerciallyavailable having 60% ethanol as its active ingredient, water as avehicle, liposome-building blocks including glycerol distearate,stearate-10, cholesterol, and polysorbate 80, sodium laureth sulfate asa surfactant, propylene glycol as a moisturizer, and preservativesincluding diazolidinyl urea, methylparaben, and propylparaben.Prevacare-D™ is a commercially available product having 60% ethanol asits active ingredient, and also includes cyclomethicone as an emollient,polyethylene and silica as viscosity builders, mineral oil as amoisturizer/emollient, propylparaben as a preservative and fragrance.

A principal drawback with the increased use of alcohol-based productssuch as Avagard™, Prevacare™, or others presently available or embodiedin various issued U.S. or European patents (see e.g. U.S. Pat. Nos.3,485,915, 4,478,853, 4,956,170, 5,403,864, 5,516,510, 5,776,430,5,885,562, 5,951,993, 6,022,551, 6,107, 261, 6,136,771, 6,204,230,6,352,701, and European Patent Application 0604 848) is that certainingredients in the formulations, including the alcohol itself, may causeirritation and allergic reactions on the skin. This drawback was readilyapparent in a recent study of alcohol-based disinfectants among nurses,which showed that adverse reactions occurred in approximately 12% of allindividuals following exposure to these products (Cimiotti et al., 2003,Am. J. Infect. Control 31:43-48.). The instant invention provides onemeans of overcoming this problem. Certain zinc salts may be added toalcohol-based gels, hand scrubs or other products to prevent theirritation that may otherwise be caused by the alcohol or other activeor inactive ingredients that they may contain (see e.g. U.S. Pat. Nos.5,965,610 and 5,985,918, the contents of which are incorporated byreference herein).

Transmission of infectious diseases is also a serious public healthconcern outside of the health care setting. For example, a growingnumber of infectious agents may be transmitted by sexual contact, andpublic health experts increasingly advocate the use of various devicesor substances to reduce or prevent the transmission of infectious agentsduring sexual contact. Unfortunately, such devices or substances oftencontain irritating components or ingredients that may cause irritationor the dermis or mucous membranes, thereby actually increasing the riskof infection. For example, male or female condoms are often made fromlatex or other potentially irritating substances. Genital creams,lotions or ointments often contain potentially irritating microbicides,fungicides or spermicides.

In the present invention, specific combinations of two or morewater-soluble organic salts of zinc have been identified that areeffective in preventing irritation caused by spermicides, microbicides,and alcohol-based gels at concentrations that are low enough so that therisk of zinc toxicity, inactivation of therapeutic compounds, and dermaland/or mucosal irritation are minimized.

It is well known that zinc salts exert numerous biological effects. Forexample, zinc is essential for normal growth and cognitive developmentin mammals, and zinc deficiency has been implicated in a host ofpathophysiological states in humans, including cognitive impairment,ocular dysfunction, eating disorders and immune dysfunction among manyothers.

Considering the myriad effects of zinc in humans, it is unlikely that asingle mechanism could account for them all. However, one of the mostimportant functions of zinc in vivo may be as a part of metalloproteinsknown as “zinc finger” proteins. Zinc finger proteins contain cysteine-and/or histidine-rich domains comprised of an α helix and two β strandsin an antiparallel orientation that are held together electrostaticallyby a divalent zinc cation (Zn²⁺). Zinc finger domains are commonly foundon proteins that bind to and interact with RNA or DNA. Because zincfinger proteins are essential regulators of cell proliferation, it iseasy to understand, at least superficially, how zinc could be crucialfor normal growth and cognitive development, which requires largeamounts of cell growth. This same mechanism may also explain why zinc isrequired for normal immune function, since rapid proliferation ofvarious cellular elements of the immune system, such as T-cells and/orB-cells, occurs in response to the presentation of foreign antigens.

Zinc may also play a less direct and less specific role in immunefunction and other biological processes. Proteins are comprised oflinear chains of amino acids, some of which are positively-charged, someof which are negatively-charged, and some of which are neutral. Whensuch a linear chain is allowed to move freely in three-dimensions,constrained only by the peptidic linkages between the individual aminoacids, complex three-dimensional structures result. Proteins may assumeunique shapes that allow them to interact with other proteins havingcomplementary shapes, the so-called “lock-and-key” theory ofprotein-protein interactions. However, due to the distribution ofcharged amino acids, proteins may also have unique electricalconfigurations that can govern their interactions with othercomplexly-charged protein molecules. Zinc ions, by binding tonegatively-charged regions exposed on the surface of proteins, may alterthe charge configuration of the protein and prevent subsequentprotein-protein interactions. One practical consequence of thisphenomenon, for example within the context of immune function, may bethe ability of zinc ions to block the binding of viruses or otherpathogens to specific receptors on the cell surface, thus preventinginfection.

This latter mechanism may account for the known properties of zinc saltsas anti-irritants. Irritation of the skin may ensue following thebinding, either specific or non-specific, or proteinaceous ornon-proteinaceous compounds to the epithelial cells comprising thesurface layer of the skin or mucosa. A large number of people are knownto exhibit irritant dermatitis when their skin is exposed to variouschemicals, antiseptics (chlorhexidine, quaternary ammonium compound andchlorinated phenols), disinfectants such as alcohol, biological fluids(urine), latex gloves etc. Zinc salts may prevent irritation by alteringthe charge configuration of the irritant, thereby preventing itssubsequent binding to the underlying tissue.

A number of U.S. patents relate to the incorporation of zinc salts invarious gel compositions to prevent irritation. For example, U.S. Pat.No. 5,708,023 discloses the use of a gel wherein zinc gluconatecomprises the sole gelling agent as a method of preventing skinirritation. Antimicrobial agents may also be incorporated into thesegels. However, the relatively high concentrations of zinc (10% to 50% byweight) found in these gels makes them less desirable for internal use,where the diffusion of the water-soluble zinc salt creates the potentialfor systemic zinc toxicity, which can be manifested as emesis,irritation and corrosion of the gastrointestinal tract, acute renaltubular necrosis and interstitial nephritis.

U.S. Pat. Nos. 5,965,610 and 6,037,386, both entitled “Composition forinactivating irritants in fluids,” also disclose compositions containingwater-soluble zinc salts such as zinc gluconate, zinc acetate, zincsulfate, zinc undecylinate and zinc salicylate for use asanti-irritants. When used at high concentrations, these zinc salts canlargely prevent irritant dermatitis. Again, these compositions are lesssuited to internal use due to their relatively high concentrations ofzinc (2% or more of zinc oxide or other zinc salts).

U.S. Pat. No. 5,985,918, entitled “Zinc-based anti-irritant creams,”relates the use of organic salts of zinc in anti-irritant creams. In thecompositions disclosed in this patent, at least 1% and more preferably5% or more of zinc salts were needed for the products to be completelyeffective as anti-irritants.

Apart from the potential for systemic zinc toxicity following theabsorption of high concentration water-soluble zinc salts through theskin or mucosa following their use in topical creams or gels, zincitself may be an irritant at high concentrations. Thus, there is apractical upper limit to the amount of zinc that may be contained withinanti-irritant creams and lubricants, especially those designed forinternal use. The existence of a practical upper limit on the amount ofzinc that is desirable for incorporation into contraceptive orantiseptic creams is further evident from the fact that, through itsability to bind to and subsequently inactivate potential irritants suchas the contraceptive or antiseptic agent, the inclusion of highconcentrations of zinc salts in these products may render themineffective for their intended functions.

U.S. Patent No. 5,980,477 of Kelly, entitled “Genital lubricants withzinc salts as anti-viral additives,” relates to the incorporation ofwater-soluble, organic salts of zinc, at concentrations ranging from0.5%-30%, into genital lubricants or other similar products toeffectuate the inactivation of HIV-1 or other viruses implicated in thespread of sexually-transmitted diseases. At the upper limit of the zincconcentration range, there may be an increased risk of zinc toxicity, aswell as the potential for vaginal irritation caused by the directirritant effects of zinc. The effectiveness of the contraceptive agentsalso may be compromised. Furthermore, Kelly does not appreciate ordescribe the beneficial anti-irritant effects of low concentrations ofcombinations of water-soluble, organic salts of zinc.

In the present invention, specific combinations of two or morewater-soluble organic salts of zinc have been identified that areeffective in preventing irritation caused by spermicides, microbicides,and alcohol-based gels at concentrations that are low enough so that therisk of zinc toxicity, inactivation of therapeutic compounds, andmucosal irritation are minimized. The incorporation of zinc saltcombinations into contraceptive or antiseptic lubricants or creams willthus render these products less irritating to the underlying mucosa, andtherefore better able to protect against the contraction of infectiousdiseases, while maintaining the effectiveness of these products fortheir intended use.

3. SUMMARY OF THE INVENTION

The present invention relates to combinations of water-soluble zincsalts which, when intermixed with gels, creams, lotions or ointmentsthat are then applied to the skin or other surface, can minimize orprevent irritation to the skin. When added to water- or alcohol-basedtopical disinfectants, the anti-irritant properties of the zinc saltsdescribed herein may increase the use of topical disinfectantscontaining zinc salts among health care workers, thereby reducing thetransmission of infectious diseases in hospital settings. These samezinc salt combinations may be added to gels, creams or lubricantscontaining spermicides, microbicides, fungicides or otherpotentially-irritating therapeutic agents, to reduce or prevent theirritation of skin or mucosal membranes caused by these therapeuticagents. When employed in genital lubricants, the reduction in irritationof the vaginal mucosa may assist in minimizing the spread ofsexually-transmitted diseases.

The invention is based, at least in part, on the following twodiscoveries. First, the addition of combinations of low concentrationsof water-soluble organic salts of zinc to gels, creams, lotions orointments applied topically were found to increase the ability of theseproducts to prevent irritants from achieving contact with the underlyingskin, thus reducing irritation. Second, the addition of combinations oflow concentrations of water-soluble organic zinc salts to genitallubricants were observed to reduce the irritation of mucous membranescaused by the presence of potentially-irritating substances such asspermicides, microbicides, fungicides or other therapeutic agents withinthe lubricant. Preferred embodiments of the invention include topicalantimicrobial compositions that lack conventional antibiotics orpreservatives, wherein the antimicrobial benefit is created by essentialoils (or their active ingredients), emollient solvents and, in someinstances, anti-inflammatory agents.

4. DETAILED DESCRIPTION OF THE INVENTION

The present invention relates, at least in part, to methods andcompositions for the prevention of the irritation of skin or mucosalsurfaces that may occur as a result of exposure to irritant substances.It is based, at least in part, on the discovery that the addition ofcombinations of water-soluble, organic salts of zinc to gels, creams,lotions, or ointments can increase the ability of these gels, creams,lotions or ointments to prevent irritants from causing irritation of theunderlying substrate. While it had been found previously that highconcentrations of zinc salts added to gels, creams, lotions or ointmentsmay enhance the protective effects of these products, zinc itself athigh concentrations has been shown to produce irritation. Furthermore,high concentrations of zinc ions in these products also raise thepotential for local or systemic zinc toxicity in subjects who use theseproducts. One surprising aspect of the instant invention, therefore, isthe finding that low concentrations of zinc salts, especially when twoor more such salts are used in combination, can achieve a satisfactorydegree of anti-irritant effect while minimizing the potential for bothzinc-induced irritation and toxicity. A further advantage of the presentapproach is that the concentrations of the combination of zinc saltsadvocated in the present invention are sufficiently low so that theiraddition to gels, creams, lotions or ointments containingbiologically-active agents such as spermicides, microbicides, fungicidesor other potentially-irritating therapeutic compounds may not beexpected to result in the inactivation of these compounds, therebypermitting their use as anti-irritant agents in gels, creams, lotions orointments containing these compounds.

Accordingly, in various embodiments, the present invention provides foranti-irritant gels, creams, lotions or ointments comprising lowconcentrations of two or more water-soluble, organic salts of zinc thatare effective in preventing or reducing irritation.

The term “low concentration” means percentages of free zinc ions (Zn²⁺)in the gel, cream, lotion or ointment at less than 0.5% on a weight toweight (w/w) basis.

Suitable zinc salts for use in these compositions include zinc acetate(molar solubility in water of 1.64 moles/l), zinc butyrate (molarsolubility in water of 0.4 moles/l), zinc citrate (molar solubility inwater of <0.1 moles/l), zinc gluconate (molar solubility in water of0.28 moles/l), zinc glycerate (moderately water soluble), zinc glycolate(moderately water soluble), zinc formate (molar solubility in water of0.33 moles/l), zinc lactate (molar solubility in water of 0.17 moles/l),zinc picolinate (moderately water soluble), zinc proprionate (molarsolubility in water of 1.51 moles/l), zinc salicylate (low watersolubility), zinc tartrate (moderately water soluble) and zincundecylenate (moderately water soluble).

The terms “prevention” or “reduction” of irritation means a decrease inobjective or subjective signs of irritation in tissues treated with thegels, creams, lotions or ointments comprising low concentrations of twoor more water-soluble, organic salts of zinc of at least 50%, and morepreferably by greater than 90% relative to control tissues exposed tothe irritant agent and the same gels, creams, lotions or ointmentslacking zinc salts. Irritation in this context may be evidenced byredness or other changes in coloration, inflammation or swelling,hypersensitivity, the occurrence of burning, itching or other painfulstimuli, or other macroscopic or microscopic changes known to those ofordinary skill in the art to be associated with irritation.

The formulations of the invention (which include, but are not limitedto, gels, creams, lotions, lubricants, elixirs, oils, emulsions,ointments, soaps, scrubs, liquids, pastes and the like) may be appliedtopically to the skin or to the various mucous membranes of the body,including but not limited to those of the oral, nasal, vaginal or rectalcavities, to prevent the effects of exogenous irritants upon thesesurfaces.

In preferred embodiments, the gel or cream comprises a mixture of water,a gelling agent, a thickening agent, a hydrophilic or hydrophobicpolymer, an emulsifying agent, and an emollient. The zinc salts comprisea combination of effective amounts of two or more of the following: zincacetate (0.1-2.0%), zinc citrate (0.1-2.0%), zinc gluconate (0.1-2.0%)and zinc lactate (0.1-2.0%). In preferred embodiments, the zinc saltsare 1% zinc gluconate, 0.2% or 0.4% zinc acetate and 0.2% of either zinclactate or zinc citrate.

In alternative embodiments, the gel comprises a mixture of water(10-50%), alcohol (30-90%), a zinc gel (a combination of quaternarycationic hydroxy ethyl cellulose (0.1-0.3%) and triple zinc salt mixturecontaining zinc gluconate (0.1-2.0%), zinc acetate (0.1-2.0%) and zinclactate (0.05-2.0%)) and emollients (0.3-1%).

In further embodiments, the cream comprises a mixture of water (10-50%),petroleum jelly (10-40%), crothix (0.5-3%), allantoin (0.3-1.0%),salicylic acid (1.0-4.0%), dimethicone (0.5-5.0%), zinc stearate(1.0-5.0%), zinc oxide (0.5-5.0%), a triple zinc salt mixture containingzinc gluconate (0.1-2.0%), zinc acetate (0.1-2.0%) and zinc lactate(0.05-2.0%), and other emollients (10-30%).

In further embodiments, the lotion comprises a mixture of water(60-80%), petroleum jelly (2-10.0%), crothix (0.5-2.0%), crodomol MM(0.5-2.01%), cremerol (0.5-2.0%), zinc stearate (1.0-5.0%), zinc oxide(0.1-3.0%), a triple zinc salt mixture containing zinc gluconate(0.05-2.0%), zinc acetate (0.05-2.0%) and zinc lactate (0.05-2.0%), andemollients (10-30%). In preferred embodiments, the zinc salts are 0.3%zinc gluconate, 0.1 % zinc acetate and 0.1 % of zinc lactate

The present invention further relates to hydroalcoholic gel compositionscomprising combinations of 1% or less of hydrogel dissolved in water atambient temperature and 3% or less of emollient dissolved in alcohol or3% or less of emulsifier wherein said compositions have viscositiesbelow 4000 centipoise (cps) at between 20-40° C. These percentages andfurther percentages discussing these hydroalcoholic gel compositionsshould be considered weight/weight percentages, unless otherwisespecified. In preferred embodiments of the invention such compositionscomprise 30-80% alcohol, 15-70% water, 0.05-0.5% hydrogel, and 0.2-3.0%emollient and/or 0.05-0.5% emulsifier with viscosities of less than 2000cps, most preferably between 50-500 cps. Additional embodiments of thisinvention further include silicone polymer, emollient solvent,antimicrobial agent, and thickening agent, while maintaining the lowviscosities as preferred.

Various embodiments of the invention may comprise an emollient, such as,but not limited to, PEG 20 almond glycerides, Probutyl DB-10, GlucamP-20, Glucam E-10, Glucam P-10, Glucam E-20, Glucam P-20 distearate,glycerin, propylene glycol, cetyl acetate, and acetylated lanolinalcohol, cetyl ether, myristyril ether, hydroxylated milk glycerides,polyquatemium compounds, copolymers of dimethyl dialyl ammonium chlorideand acrylic acid, dipropylene glycol methyl ethers, polypropylene glycolethers and silicon polymers. Other suitable emollients may includehydrocarbon-based emollients such as petrolatum or mineral oil, fattyester-based emollients, such as methyl, isopropyl and butyl esters offatty acids such as isopropyl palmitate, isopropyl myristate, isopropylisostearate, isostearyl isostearate, diisopropyl sebacate, and propylenedipelargonate, 2-ethylhexyl isononoate, 2-ethylhexyl stearate, C₁₂-C₁₆fatty alcohol lactates such as cetyl lactate and lauryl lactate,isopropyl lanolate, 2-ethylhexyl salicylate, cetyl myristate, oleylmyristate, oleyl stearate, oleyl oleate, hexyl laurate, and isohexyllaurate. Additional useful emollients include lanolin, olive oil, cocoabutter, and shea butter. Preferred emollient solvents of the inventioninclude octoxyglycerin (Sensiva®), pentylene glycol, 1,2 hexanediol andcaprylyl glycol.

Various embodiments of the invention may comprise a stabilizing agent,such as, but not limited to, an antioxidant (which may be at aconcentration of 0.2-1%), such as but not limited to vitamin C (ascorbicacid) or vitamin E (tocopherol).

Various embodiments of the invention may comprise a surfactant (whichmay be at a concentration of 0.2-1.0%), such as but not limited toincromide or silicone-based surfactants (Masil SF-19, BASF). Thestabilizing agents surprisingly appear to remove the turbidity of thegel, cream, lotion or ointment, resulting in a clear product thatimparts a light feel to the surface to which it is applied.

Various embodiments of the invention may comprise a thickening agent,such as but not limited to the following (at a preferred concentrationof 0.6-2%): stearyl alcohol, cationic hydroxy ethyl cellulose (Ucare;JR30), hydroxy propyl methyl cellulose, hydroxy propyl cellulose(Klucel), chitosan pyrrolidone carboxylate (Kytamer), behenyl alcohol,zinc stearate, or an emulsifying wax such as but not limited toIncroquat and Polawax. Other thickening and/or gelling agents suitablefor incorporation into the anti-irritant gels, creams, lotions orointments described herein include, for example, an addition polymer ofacrylic acid, a resin such as Carbopol® ETD™ 2020, guar gum, acacia,acrylates/steareth-20 methacrylate copolymer, agar, algin, alginic acid,ammonium acrylate co-polymers, ammonium alginate, ammonium chloride,ammonium sulfate, amylopectin, attapulgite, bentonite, C9-15 alcohols,calcium acetate, calcium alginate, calcium carrageenan, calciumchloride, caprylic alcohol, carbomer 910, carbomer 934, carbomer 934P,carbomer 940, carbomer 941, carboxymethyl hydroxyethyl cellulose,carboxymethyl hydroxypropyl guar, carrageenan, cellulose, cellulose gum,cetearyl alcohol, cetyl alcohol, corn starch, crodomol, crothix, damar,dextrin, dibenzlidine sorbitol, ethylene dihydrogenated tallowamide,ethylene diolamide, ethylene distearamide, gelatin, guar gum, guarhydroxypropyltrimonium chloride, hectorite, hyaluronic acid, hydratedsilica, hydroxybutyl methylcellulose, hydroxyethylcellulose,hydroxyethyl ethylcellulose, hydroxyethyl stearamide-MIPA, isocetylalcohol, isostearyl alcohol, karaya gum, kelp, lauryl alcohol, locustbean gum, magnesium aluminum silicate, magnesium silicate, magnesiumtrisilicate, methoxy PEG-22/dodecyl glycol copolymer, methylcellulose,microcrystalline cellulose, montmorillonite, myristyl alcohol, oatflour, oleyl alcohol, palm kernel alcohol, pectin, PEG-2M, PEG-5M,polyacrylic acid, polyvinyl alcohol, potassium alginate, potassiumaluminium polyacrylate, potassium carrageenan, potassium chloride,potassium sulfate, potato starch, propylene glycol alginate, sodiumacrylate/vinyl alcohol copolymer, sodium carboxymethyl dextran, sodiumcarrageenan, sodium cellulose sulfate, sodium chloride, sodiumpolymethacylate, sodium silicoaluminate, sodium sulfate, stearalkoniumbentonite, stearalkonium hectorite, stearyl alcohol, tallow alcohol,TEA-hydrochloride, tragacanth gum, tridecyl alcohol, tromethaminemagnesium aluminum silicate, wheat flour, wheat starch, xanthan gum,abietyl alcohol, acrylinoleic acid, aluminum behenate, aluminumcaprylate, aluminum dilinoleate, aluminum salts, such as distearate, andaluminum isostearates, beeswax, behenamide, butadiene/acrylonitrilecopolymer, C29-70 acid, calcium behenate, calcium stearate, candelillawax, carnauba, ceresin, cholesterol, cholesterol hydroxystearate,coconut alcohol, copal, diglyceryl stearate malate, dihydroabietylalcohol, dimethyl lauramine oleate, dodecanoic acid/cetearylalcohol/glycol copolymer, erucamide, ethylcellulose, glyceryl triacetylhydroxystearate, glyceryl tri-acetyl ricinolate, glycol dibehenate,glycol di-octanoate, glycol distearate, hexanediol distearate,hydrogenated C6-14 olefin polymers, hydrogenated castor oil,hydrogenated cottonseed oil, hydrogenated lard, hydrogenated menhadenoil, hydrogenated palm kernel glycerides, hydrogenated palm kernel oil,hydrogenated palm oil, hydrogenated polyisobutene, hydrogenated soybeanoil, hydrogenated tallow amide, hydrogenated tallow glyceride,hydrogenated vegetable glyceride, hydrogenated vegetable oil, Japan wax,jojoba wax, lanolin alcohol, shea butter, lauramide, methyldehydroabietate, methyl hydrogenated rosinate, methyl rosinate,methylstyrene/vinyltoluene copolymer, microcrystalline wax, montan acidwax, montan wax, myristyleicosanol, myristyloctadecanol,octadecene/maleic anhyrdine copolymer, octyldodecyl stearoyl stearate,oleamide, oleostearine, ouricury wax, oxidized polyethylene, ozokerite,paraffin, pentaerythrityl hydrogenated rosinate, pentaerythrityltetraoctanoate, pentaerythrityl rosinate, pentaerythrityl tetraabietate,pentaerythrityl tetrabehenate, pentaerythrityl tetraoleate,pentaerythrityl tetrastearate, ophthalmic anhydride/glycerin/glycidyldecanoate copolymer, ophthalmic/trimellitic/glycols copolymer,polybutene, polybutylene terephthalate, polydipentene, polyethylene,polyisobutene, polyisoprene, polyvinyl butyral, polyvinyl laurate,propylene glycol dicaprylate, propylene glycol dicocoate, propyleneglycol diisononanoate, propylene glycol dilaurate, propylene glycoldipelargonate, propylene glycol distearate, propylene glycoldiundecanoate, PVP/eiconsene copolymer, PVP/hexadecene copolymer, ricebran wax, stearlkonium bentonite, stearalkonium hectorite, stearamide,stearamide DEA-distearate, stearamide DIBA-stearate, stearamideMEA-stearate, stearone, stearyl erucamide, stearyl stearate, stearylstearoyl stearate, synthetic beeswax, synthetic wax, trihydroxystearin,triisononanoin, triisostearin, tri-isostearyl trilinoleate, trilaurin,trilinoleic acid, trilinolein, trimyristin, triolein, tripalmitin,tristearin, zinc laurate, zinc myristate, zinc neodecanoate, zincrosinate, and mixtures thereof.

An embodiment of the invention may comprise phenoxyethanol (0.3-1.0%) asa solubilizing agent.

Various embodiments of the invention may comprise a humectant, such asbut not limited to glycerin, 1-2-propylene glycol, dipropylene glycol,polyethylene glycol, 1,3-butylene glycol, or 1,2,6-hexanetriol.

Various embodiments of the invention may comprise one or moreantimicrobial or preservative agent, preferably at a concentrationbetween 0.05 and 2%. Examples of preferred antimicrobial and/orpreservative agents include, but are not limited to, chlorhexidinegluconate (CHG), benzalkonium chloride (BZK), or iodopropynylbutylcarbamate (IPBC; Germall plus). Further examples of antimicrobial agentsinclude, but are not limited to, iodophors, iodine, benzoic acid,dihydroacetic acid, propionic acid, sorbic acid, methyl paraben, ethylparaben, propyl paraben, butyl paraben, cetrimide, quaternary ammoniumcompounds, including but not limited to benzalkonium chloride,dequalinium chloride, biguanides such as chlorhexidine (including freebase and salts (see below)), chloroeresol, chlorxylenol, benzyl alcohol,bronopol, chlorbutanol, ethanol, phenoxyethanol, phenylethyl alcohol,2,4-dichlorobenzyl alcohol, thiomersal, clindamycin, erythromycin,benzoyl peroxide, mupirocin, bacitracin, polymyxin B, neomycin,triclosan, parachlorometaxylenol, foscarnet, miconazole, fluconazole,itriconazole, ketoconazole, and pharmaceutically acceptable saltsthereof.

Pharmaceutically acceptable chlorhexidine salts that may be used asantimicrobial agents according to the invention include, but are notlimited to, chlorhexidine palmitate, chlorhexidine diphosphanilate,chlorhexidine digluconate, chlorhexidine diacetate, chlorhexidinedihydrochloride, chlorhexidine dichloride, chlorhexidine dihydroiodide,chlorhexidine diperchlorate, chlorhexidine dinitrate, chlorhexidinesulfate, chlorhexidine sulfite, chlorhexidine thiosulfate, chlorhexidinedi-acid phosphate, chlorhexidine difluorophosphate, chlorhexidinediformate, chlorhexidine dipropionate, chlorhexidine di-iodobutyrate,chlorhexidine di-n-valerate, chlorhexidine dicaproate, chlorhexidinemalonate, chlorhexidine succinate, chlorhexidine malate, chlorhexidinetartrate, chlorhexidine dimonoglycolate, chlorhexidine monodiglycolate,chlorhexidine dilactate, chlorhexidine di-a-hydroxyisobutyrate,chlorhexidine diglucoheptonate, chlorhexidine di-isothionate,chlorhexidine dibenzoate, chlorhexidine dicinnamate, chlorhexidinedimandelate, chlorhexidine di-isophthalate, chlorhexidinedi-2-hydroxynapthoate, and chlorhexidine embonate. Chlorhexidine freebase is a further example of an antimicrobial agent.

These and further examples of antimicrobial agents useful in thisinvention can be found in such references as Goodman and Gilman's ThePharmacological Basis of Therapeutics (Goodman Gilman A, Rall T W, NiesA S, Taylor P, ed. (Pergamon Press; Elmsford, N.Y.: 1990)), the contentsof which are hereby incorporated by reference.

In one preferred embodiment, a composition of the invention comprises 1%chlorhexidine and a combination of at least two or more of thefollowing: zinc acetate (0.1-2.0%), zinc citrate (0.1-2.0%), zincgluconate (0.1-2.0%) and zinc lactate (0.1-2.0%). In another preferredembodiment, a composition of the invention comprises 2% miconazole and acombination of at least two or more of the following: zinc acetate(0.1-2.0%), zinc citrate (0.1-2.0%), zinc gluconate (0.1-2.0%) and zinclactate (0.1-2.0%).

Various embodiments of the invention may comprise a neutralizing agentto neutralize carboxyl groups present in one or more other component,such as carboxyl groups in a thickening agent. Suitable neutralizingagents include diisopropylamine and triethanolamine.

Various embodiments of the invention may comprise a surfactant. Thesurfactant may be an anionic surfactant, a cationic surfactant, anampholytic surfactant, or a nonionic surfactant. Examples of nonionicsurfactants include polyethoxylates, fatty alcohols (e.g., ceteth-20 (acetyl ether of polyethylene oxide having an average of about 20 ethyleneoxide units) and other “BRIJ”® nonionic surfactants available from ICIAmericas, Inc. (Wilmington, Del.)), cocamidopropyl betaine, alkylphenols, fatty acid esters of sorbitol, sorbitan, or polyoxyethylenesorbitan. Suitable anionic surfactants include ammonium lauryl sulfateand lauryl ether sulfosuccinate. A preferred surfactant is lauroylethylenediamine triacetic acid sodium salt at a concentration betweenabout 0.5-2.0%. Suitable concentrations of surfactant are between about0.05% and 2%.

Water used in the formulations described herein is preferably deionizedwater having a neutral pH. When used in hydroalcoholic gel compositions,the concentration of water should be suitable to dissolve the hydrogelsaccording to the invention.

Various embodiments of the invention may comprise additional additives,including but not limited to a silicone fluid (such as dimethicone orcyclomethicone), dyes, fragrances, pH adjusters, including basic pHadjusters such as ammonia, mono-, di- and tri-alkyl amines, mono-, di-and tri-alkanolamines, alkali metal and alkaline earth metal hydroxides(e.g., ammonia, sodium hydroxide, potassium hydroxide, lithiumhydroxide, monoethanolamine, triethylamine, isopropylamine,diethanolamine and triethanolamine); acid pH adjusters such as mineralacids and polycarboxylic acids (e.g., hydrochloric acid, nitric acid,phosphoric acid, sulfuric acid, citric acid, glycolic acid, and lacticacid); vitamins such as vitamin A, vitamin E and vitamin C; polyaminoacids and salts, such as ethylenediamine tetraacidic acid (EDTA),preservatives such as Germall plus and DMDM hydantoin, and sunscreenssuch as aminobenzoic acid, arobenzone, cinoxate, diioxybenzone,homosalate, menthyl anthranilate, octocrylene, octyl methoxycinnamate,octyl salicylate, oxybenzoate, padimate O, phenylbenzimidazole, sulfonicacid, sulisobenzone, titanium dioxide, trolamine salicylate and zincoxide.

Various embodiments of the invention may comprise an essential oil(“EO”), which is a volatile oil obtained from a plant or an animalsource that comprises one or more active agent (also referred to hereinas an Isolated Component or “IC”) which may be, for example but not byway of limitation, a monoterpene or sesquiterpene hydrocarbon, alcohol,ester, ether, aldehyde, ketone, or oxide. Examples of these EOs include,but are not limited to, almond oil, ylang-ylang oil, neroli oil,sandalwood oil, frankincense oil, peppermint oil, lavender oil, jasmineabsolute, geranium oil bourbon, spearmint oil, clove oil, lemongrassoil, cedarwood oil, balsam oils, and tangerine oil. Alternatively, thepresent invention provides for the use of active agents found inessential oils (ICs) such as, but not limited to, 1-citronellol,α-amylcinnamaldehyde, lyral, geraniol, farnesol, hydroxycitronellal,isoeugenol, eugenol, eucalypus oil and eucalyptol, lemon oil, linalool,and citral. Apart from their effects as fragrances or flavorants, suchcompounds also may be useful in the instant invention as antimicrobialagents.

A hydrogel, as used herein, may comprise hydroxypropylmethyl cellulose,cationic hydroxyethyl cellulose (U-care polymers), ethyl cellulose,hydroxypropyl cellulose, hydroxymethyl cellulose, carboxy methylcellulose, polyethylene oxide (polyox resins), or chitosan pyrrolidonecarboxylate (Kytomer PC). These hydrogels preferably do not adverselybind to any added antimicrobial agent, therefore leaving the optionallyadded antimicrobial agent free for rapid and long-term activity. Inaddition, it has been discovered that alcohol used to form thehydroalcoholic gel is not trapped in the hydroalcoholic gel compositionand is therefore available for rapid and long-term action. The hydrogelmay be present in a concentration between 0.1-1.0%, and preferably is acationic hydroxyethyl cellulose (U-care polymers) in a concentrationbetween 0.05-0.5%, most preferably 0.2%.

In hydroalcoholic gel compositions of the invention, alcohols that maybe used include aliphatic alcohols, including, but not limited to,ethanol, isopropyl alcohol, n-propyl alcohol, and mixtures thereof;fatty alcohols, including, but not limited to, cetyl alcohol, myristolalcohol, stearyl alcohol, octyl alcohol, decyl alcohol and laurylalcohol, and mixtures thereof; and hexanol. The concentration of alcoholmay be between 30% and 95%, preferably between 40% and 70%; preferablythe aliphatic alcohols is ethanol or isopropyl alcohol at aconcentration between and 60% and 95%. When present, the concentrationof fatty alcohols is preferably between 0.5% and 5.0%; and, whenpresent, the concentration of hexanol is preferably between 3% and 10%,more preferably 5%.

Hydroalcoholic gel compositions of the invention may optionally comprisean emollient and/or humectant such as the emollients and humectantsdiscussed above, preferably one or more of PEG 20 Almond Glycerides,Probutyl DB-10, Glucam P20, Glucam E-10, Glucam P-10, Glucam E-20,Glucam P-20 distearate, glycerin, propylene glycol, octoxyglycerin(Sensiva®), cetyl acetate and acetylated lanolin alcohol (Acetulan),cetyl ether (PPG-10), myristyl ether (PPG-3), hydroxylated milkglycerides (Cremerol HMG), polyquatemium compounds (U-care compounds),chitosan (Kytamer), copolymer of dimethyl dialyl ammonium chloride andacrylic acid (Merquat), dipropylene glycol methyl ethers (Dowanol DPMDow Coming), or polypropylene glycol ethers (Ucon 50-HB-660, UnionCarbide). Preferably the emollient is present at a concentration of 3%or less, such that the viscosity of the composition is preferably lessthan 2000 centipoise at 20-40° C., more preferably between 0.2 and 3%.

Hydroalcoholic gel compositions of the invention may optionally comprisea surfactant and/or emulsifier, such as the emulsifiers and surfactantsdiscussed above, and preferably a non-ionic or cationic self-emulsifyingwax that is soluble in alcohol at ambient temperature. Suitablesurfactant/emulsifiers include but are not limited to Incroquat BehenylTMS, Incroquat Behenyl TMS-50, Polawax, stearyl alcohol and cetearylalcohol. These emulsifiers may be present at a concentration between0.05-3.0%. Preferred emulsifiers include Incroquat Behenyl TMS, which isa mild cationic emulsifier as well as an excellent conditioner, andPolawax, which is a non-ionic self emulsifying wax, individually at aconcentration of between 0.05-0.5%, and in combination at aconcentration of between 0.05-0.5%, more preferably in combination at aconcentration ratio of approximately 1:1. If more than one emulsifier isused, it is preferred that the total concentration of emulsifierspresent is between 0.05-0.5%.

A hydroalcoholic gel of the invention may optionally comprise a siliconepolymer such as, but not limited to, one or more than onepolydimethylsiloxane polymer (Dow Coming 225 Silicone Fluid),dimethiconol fluid in dimethicone (Dow Coming 1403 Silicone Fluid),cyclomethicone and dimethicone copolyl (Dow Coming 3225C SiliconeFluid), or silicone glycol (BASF 1066 DCG polyol). Preferredconcentrations of silicone polymer are between about 0.1-1.0%.

A hydroalcoholic gel of the invention may optionally comprise anemollient solvent such as, but are not limited to, those listed above orone or more than one glycidyl ethers having alkyl chains up to andincluding 18 carbon molecules and ethoxylates and propoxylates thereof,glyceryl ethers having alkyl chains up to and including 18 carbonmolecules and ethoxylates and propoxylates thereof, mono- and diglycerylethers having alkyl chains up to and including 18 carbon molecules andethoxylates and propoxylates thereof, ethoxylate and propoxylate ethers,ethoxy diglycol esters, ethyl hexyl alcohol propoxylate, propyleneglycol esther ethoxylates or propoxylates, or, preferably Arlamol(Altas). Preferred concentrations of emollient solvent are between0.5-5%.

A hydroalcoholic gel of the invention may optionally comprise athickening agent, such as, but not limited to, a thickening and/orgelling agent discussed above, preferably behenyl alcohol, crodomol, orcrothix. Preferred concentrations of thickening agent are between0.05-10%. Gelling agents such as Caropol are not preferred due to theirhigh viscosity and their requiring neutralizing agents to neutralize thegelling agent with alkaline materials.

A hydroalcoholic gel of the invention may optionally comprise one ormore antimicrobial agent, such as those set forth above. Preferably, theconcentration of the one or more than one antimicrobial agent is lessthan 3%. In particular non-limiting embodiments of the invention,hydroalcoholic gels may comprise chlorhexidine gluconate, benzalkoniumchloride and phenoxyethanol, preferably at a concentration of between0.05-0.5%, 0.1-0.25%, and 0.1-1.0%, respectively. Because cationicantimicrobials, such as biguanides and quaternary ammonium compounds,can bind to the surface of the skin, they may not be available toinactivate pathogens that come into contact with the skin. The gelformulation according to the invention preferably forms a film on thesurface of the hand when applied, which film acts as a barrierpreventing the antimicrobial agents that may be added to the gel frombinding to the surface of the skin.

Ambient temperature is defined herein between 20 and 35° C. Roomtemperature is defined herein between 20 and 25° C.

The present invention further provides for spermicidal gels, creams,lubricants, lotions or ointments containing low concentrations of two ormore water-soluble, organic salts of zinc that are effective in reducingor preventing the irritation caused by the spermicidal agent. Suchformulations may be applied topically to the skin or mucosa of theurogenital, perineal area, or to the surface of latex articles such asmale or female condoms, to prevent the irritating effects of spermicidesthat are incorporated into the gel. These products have the additionaladvantage of minimizing or preventing irritation caused by allergicreaction to latex. Spermicidal agents are well known to those ofordinary skill in the art, and include, but are not limited to,detergent-based spermicides. In a preferred embodiment, the spermicideis nonoxynol-9 and the zinc salts comprise a combination of two or moreof the following: zinc acetate (0.1-0.3%), zinc citrate (0.1-0.3%), zincgluconate (0.1-2.0%) and zinc lactate (0.1-0.3%). In a preferredembodiment, the zinc salts are 0.3% zinc gluconate, 0.1% zinc acetateand 0.1% zinc lactate.

In non-limiting embodiments, a composition of the invention may comprisea pre-existing formulation, such as a commercially available cream,liquid, gel or lotion. Examples of commercially available formulationsthat may be so used include, but are not limited to, personal lubricantssold under the trade names “KY JELLY,” “ASTROGLIDE,” and “PREVACARE” andlotions sold under the trade names “SOFT-SENSE,” “LOTION SOFT,” “CUREL,”and “KERI”. SOFT-SENSE (Johnson & Son, Inc., Racine, Wis.) is known tocontain purified water, glycerin USP, distearyldimonium chloride,petrolatum USP, isopropyl palmitate, 1-hexadecanol, tocopheryl acetate(vitamin E USP), dimethicone, titanium dioxide USP, methyl paraben,propyl paraben, sodium chloride, and fragrance. LOTION SOFT (CalgonVestal, St. Louis, Mo.) is a nonionic moisturizing lotion which is knownto contain mucopolysaccharide. CUREL (Bausch & Lomb Incorporated,Rochester, N.Y.) is known to contain deionized water, glycerin,quatemium-5, petrolatum, isopropyl palmitate, 1-hexadecanol,dimethicone, sodium chloride, fragrance, methyl paraben, and propylparaben.

The invention provides for methods of using the foregoing compositionsto prevent irritation to an epithelial tissue (e.g. a mucosal tissue orthe skin) comprising applying an effective amount of the composition tothe surface. Examples of irritants against which protection may beafforded include, but are not limited to, those induced by physical,chemical, mechanical or biological irritants. Specific examples of theforegoing irritants include, but are not limited to, means for hairremoval (e.g. depilatories, waxing and razors), hair relaxants (e.g.sodium hydroxide, calcium hydroxide, thioglycolates), antiperspirants(e.g. aluminum chlorhydrate and other aluminium salts), dermatologicaltreatments (e.g. alpha hydroxy acids (AHAs), especially glycolic andtrichloroacetic acids), keratoyltic skin-irritating conditions (e.g.psoriasis, dandruff, etc.), infectious skin irritants (e.g. bacteria andfungi), and agents applied for therapeutic purposes. The epithelialsurface to be protected from irritation may be dermal or mucosal,including vaginal, anorectal, oral or nasal.

The invention further provides for methods of protecting againstinfection comprising applying, to an epithelial tissue such as the skinor a mucous membrane of the body, an effective amount of one of theforegoing compositions which inhibits irritation of the tissue. Examplesof infectious agents against which protection may be afforded include,but are not limited to, infectious agents associated with sexuallytransmitted diseases, including Human Immunodeficiency Virus (HIV),Human Papilloma Virus (HPV), Herpes Simplex Virus (HSV), Chlamydiatrachomatis, Neisseria gonorrhoea, Trichomonas vaginalis, and Candidaalbicans, as well as infectious agents that may be encountered in ahealth care setting, including but not limited to Staphylococcus aureus,Pseudomonas aeruginosa, Streptococcus pneumoniae, Escherichia coli,Salmonella typhimurium, Enterococcus, and Neisseria meningitidis, HIV,varicella virus and Hepatitis viruses (e.g., A, B, and C).

In non-limiting embodiments, the present invention provides for atopical composition comprising an antimicrobial composition thatcomprises an emollient solvent and an essential oil (or active component(IC) thereof). Although such topical compositions may optionally containadditional antimicrobial (including preservative) compounds, inpreferred non-limiting embodiments, the antimicrobial compositionconsists essentially of an emollient solvent and an essential oil (seethe following paragraph). Said composition may additionally comprise ananti-inflammatory agent, for example, but not limited to, salicylicacid, acetyl salicylic acid, or zinc salicylate. The topical compositionmay, or alternatively may not, comprise one or more zinc salt, which maybe a water-soluble organic zinc salt such as those listed herein. Thepresent invention further provides for methods for producing anantimicrobial effect on the skin or mucous membrane of a subject usingsuch topical compositions.

In non-limiting embodiments, the topical compositions of the precedingparagraph lack an antimicrobial agent selected from the group consistingof iodophors, iodine, benzoic acid, dihydroacetic acid, propionic acid,sorbic acid, methyl paraben, ethyl paraben, propyl paraben, butylparaben, cetrimide, quaternary ammonium compounds, including but notlimited to benzalkonium chloride, dequalinium chloride, biguanides suchas chlorhexidine (including free base and salts (see below)),chloroeresol, chlorxylenol, benzyl alcohol, bronopol, chlorbutanol,ethanol, phenoxyethanol, phenylethyl alcohol, 2,4-dichlorobenzylalcohol, thiomersal, clindamycin, erythromycin, benzoyl peroxide,mupirocin, bacitracin, polymyxin B, neomycin, triclosan,parachlorometaxylenol, foscarnet, miconazole, fluconazole, itriconazole,ketoconazole, and pharmaceutically acceptable salts thereof.

In additional embodiments, the present invention provides for ananti-irritant composition comprising two or more zinc salts atconcentrations between 0.1 and 2% and further comprising panthenol at aconcentration of between about 0.2-5%. Said composition may optionallyfurther comprise alcohol and/or one or more zinc salt, which may be awater soluble or non-water soluble zinc salt or a combination thereof.Non-limiting examples of non-water soluble zinc salts include zinc oxideand zinc stearate, as well as other zinc salts having equivalent orlower solubilities in water relative to those compounds.

In still further embodiments, the present invention provides for a zincslurry that may be applied to a latex article (such as a condom orglove) to reduce or prevent irritation. The zinc slurry may comprise,for example but not by way of limitation, two water-soluble zinc salts(as set forth above) as a concentration of between 1-5%, twowater-insoluble zinc salts (as set forth above) at a concentration of2-10%, panthenol at a concentration of 5-40%, and glycerine at aconcentration of 20-50%. Such a slurry may be mixed with a liquid, suchas a silicone fluid, in a ratio of between 1:5 to 1:10, and then appliedto the surface of the article which will be in contact with the skin.

Percentages herein are weight/weight unless specified otherwise.

5. WORKING EXAMPLES 5.1. Example 1 Evaluation of the Anti-IrritantEffect of Various Zinc Salts in a Gel Base as a Barrier to Irritantsusing Chlorophyllin Dye as the Test Model

Chlorophyllin is a dye that stains the skin a deep green color. Thestain can only be removed after several washes with soap and water.After application of a gel base (55% Propylene glycol, 44.6% Water, 0.4%Xanthum gum) containing various combinations of zinc salts (Table 1) tothe skin of human volunteers, the extent of penetration ofexternally-applied chlorophyllin dye through the gel formulations wasdetermined.

In these studies, the forearms of the human volunteers were washed withsoap and water and then dried. The gel formulation to be tested (0.1 g)was spread over a 4 cm by 4 cm area of the forearm and allowed to dryfor 5 minutes. A 3 cm by 3 cm square of paper towel (Marcal™) was dippedin a 1.5% aqueous solution of chlorophyllin and placed centrally on thearea of the skin to which the gel had been applied. The site was thencovered by plastic wrap which was immobilized via surgical tape placedaround its edges.

After 1 hour, the plastic and paper toweling were removed and theforearm was dried with a tissue by rubbing five times. An“anti-irritant” score was assigned based on the degree of coloration ofthe skin by the dye. The degree of coloration was scored as follows:0=no color, 1=slight color, 2=moderate color, 3=heavy coloration. Thesite was then rinsed under lukewarm water while rubbing ten times and apost-wash score was read. After rinsing with soap and water and dryingby blotting with dry tissue, the tests areas were scored again. Theaverage of these three scores for each condition is shown in Table 1.From these studies, the combination of 1% zinc gluconate, 0.2% zincacetate and 0.2% zinc lactate is superior to all single zinc salts andto other zinc salt combinations in preventing the penetration of the dyethrough the lubricant base and its binding to the surface of the skin.

TABLE 1 Inhibition of Chlorophyllin Penetration by Zinc Salts Scoring ofZinc salts in lubricant base* coloration 2.0% zinc gluconate 0.5 1.4%zinc gluconate 1.0 0.6% zinc gluconate 1.0 1.4% zinc lactate 1.5 1.4%zinc acetate 0.5 1.4% zinc citrate 1.0 1.0% zinc gluconate + 0.4% zincacetate 0.5 1.0% zinc gluconate + 0.2% zinc acetate + 0.2% zinc lactate0.1 1.0% zinc gluconate + 0.2% zinc acetate + 0.2% zinc citrate 0.3 0.6%zinc acetate + 0.8% zinc lactate 1.0 Control (lubricant base only) 3.5*The necessary amount of lubricant base was added to each sample toachieve 100 g.

5.2. Example 2 Evaluation of the Anti-Irritant Effect of ZincSalt-Containing Gel-based Lubricant Composition using a Strong SkinIrritant on a Volunteer

Methyl salicylate is the active ingredient in Ben-gay™ lotion. Thiscompound is known to be an irritant in certain individuals. A volunteerwho exhibits an allergic reaction to methyl salicylate was used as atest subject to evaluate the ability of gel bases containing variouszinc salt compositions to prevent methyl salicylate-mediated irritation.

In this study, 10% of Ben-gay™ lotion was mixed with 90% of lubricant(base composition was the same as in Example 1 containing various zincsalt formulations (Table 2) and 0.2 gram per site was applied at threedifferent sites located on the left and right forearms of the volunteerfor a total of six sites. After 5 min, the site was wiped with a drytissue to remove the gel formulation and the degree of irritation wasnoted. Irritation was defined as the presence of redness, which wasscored as follows: 0=no redness, 1=slight redness, 2=moderate redness,3=heavy redness. The presence of a burning sensation, if any, was alsonoted. The results of these studies are shown in Table 2.

TABLE 2 Reduction of Skin Irritation by Zinc Salts Scoring of skinreaction Zinc salt formulation (redness) 1% zinc gluconate  2.5* 0.6%zinc gluconate 1.5 0.3% zinc gluconate 1.0 1% zinc gluconate + 0.2% zincacetate 1.0 1% zinc gluconate + 0.2% zinc acetate + 0.5 0.2% zinccitrate 1% zinc gluconate + 0.4% zinc acetate + 0.2 0.2% zinc citrate*0.4% zinc acetate + 0.2% zinc citrate 0.5 0.5% zinc gluconate + 0.1%zinc acetate + 0.5 0.1% zinc citrate 0.3% zinc lactate + 0.3% zincacetate 1.5 0/3% zinc gluconate + 0.2% zinc lactate + 0.5 0.2% zincacetate 0.3% zinc gluconate + 0.1% zinc acetate + 0.5 0.1% zinc lactateControl (lubricant base only) 3.0 *Burning sensation

Based on these findings, gels incorporating zinc gluconate alone werenot able to prevent methyl salicylate-induced irritation, and in facthigher proportions of zinc gluconate may cause some burning sensationindependent of the methyl salicylate irritant. In contrast, gelsincorporating two or more of the zinc salts consisting of zincgluconate, zinc acetate, zinc lactate and zinc citrate significantlyreduced the irritant effects of methyl salicylate. One of these triplezinc salt compositions (1% zinc gluconate+0.4% zinc acetate+0.2% zinccitrate) reduced the redness induced by the methyl salicylate, but alsoproduced some burning sensation in the volunteer. Interestingly, a gelformulation containing these same three zinc salts but at a lowerconcentration (0.5% zinc gluconate+0.1% zinc acetate+0.1% zinc citrate)was nearly as effective in preventing the methyl salicylate-inducedirritation, but did not cause any burning.

5.3. Example 3 Evaluation of the Anti-Irritant Effect of ZincSalt-Containing Lubricant Compositions on Nonoxynol-9-induced Irritationof Vaginal Mucosa in a Rabbit Model

Nonoxynol-9, when present in gel-based lubricants at 9% w/w, has beenshown to be a human irritant. Nonoxynol-9 has also been shown to produceirritation of the vaginal mucosa in a rabbit model. This animal modelwas used to evaluate the anti-irritant efficacy of various zinc saltcompositions in vivo. Due to the limited number of animals available,only a limited number of zinc salt combinations could be tested. Becausezinc gluconate has been shown to prevent latex allergies, this salt wastested alone and also in combination with zinc lactate and zinc acetate,which represented one of the better combinations of zinc saltsidentified in example 2 and still contained an amount of zinc gluconatesufficient to protect against allergic reactions to latex.

In these studies, three groups of rabbits containing six animals eachreceived one of three treatments as indicated in Table 3. The zinc saltsindicated in this table were mixed in a lubricant base (base compositionwas the same as in Example 1) which also contained the spermicidal agentnonoxynol-9 (9% w/w). Two ml of the zinc salt lubricant compositionsindicated in Table 3 was instilled into the vagina of each rabbit dailyfor five consecutive days. At the end of this period, a veterinarypathologist evaluated each animal both macroscopically andmicrohistopathologically and scored the degree of vaginal irritationthat was present. Irritation was quantified as follows: 0=No irritation,1-4=Minimal Irritant, 5-8=Mild Irritation, 9-11=Moderate Irritation,12-16=Severe Irritation. The veterinary pathologist indicated that adegree of irritation represented by a score of 3 or less would not benoticeable in humans, while a score of 8 or more would be associatedwith noticeable irritation in at least some human subjects.

As shown in Table 3, gel-based lubricant containing 9% nonoxynol-9produces mild to moderate irritation of the vaginal mucosa in rabbits,and this irritation is actually exacerbated by the presence of zincgluconate (0.3% w/w) alone. In contrast, when this same proportion ofzinc gluconate is added together with zinc lactate and zinc acetate,each at 0.1% w/w, the irritating effects of nonoxynol-9 are largelyprevented. These findings suggest that this triple zinc salt combinationcan be used to prevent irritation from spermicides and microbicides, andmay also reduce latex-induced irritation when applied on the surface ofa latex condom.

TABLE 3 Reduction of Nonoxynol-9-induced Vaginal Mucosal Irritation byZinc Salts Treatment Group Score (0–16) Average 0.3% zinc gluconate 2 166 16 7 16 10.5 0.3% zinc gluconate + 3 3 3 4 3 3 3 0.1% zinc lactate +0.1% zinc acetate Negative Control - 16 7 7 6 7 6 8 lubricant base only

5.4. Example 4 Evaluation of the Effects of Zinc Salts on the DetergentActions of Nonoxynol-9

As introduced above, nonoxynol-9 is a spermicidal agent commonly used ingenital lubricants. However, this agent is known to cause irritation andabrasions of the vaginal wall, creating the counter-productive risk ofhigher rates of infection by sexually-transmitted disease-causingpathogens including viruses or bacteria. Zinc salts can be incorporatedinto nonoxynol-9-containing lubricants to prevent this irritation, butthey may also prevent the desired spermicidal effects of this compound.Thus, additional studies were performed to examined which zinc salts,and at what levels, could potentially interfere with the spermicidaleffects of nonoxynol-9.

In these studies, the ability of nonoxynol-9 to lyse red blood cells wasemployed as an indirect indicator of its spermicidal effects. Thus, anycomposition of zinc salts that prevented the nonoxynol-9-mediated lysisof red blood cells would be likely to prevent the spermicidal effects ofthis compound and therefore be unsuitable as an anti-irritant in genitallubricants containing this spermicide. Lysis was evaluated be mixing 0.5ml of a gel base formulation (60% propylene glycol, 40% water and 0.075%hydroxymethyl propyl cellulose (K-100M)) containing 8% nonoxynol-9 andthe various combinations of zinc salts shown in Table 4 with 0.5 ml ofred blood cells isolated from rats. After five minutes of incubation at37° C., the mixtures were centrifuged and the resulting supernatantswere examined for signs of red blood cell lysis. Lysis was scored asfollows: +=100% lysis, ±=50% lysis, −=no lysis.

As shown in Table 4, zinc ion concentrations of 0.28% when introduced aszinc acetate impair the ability of nonoxynol-9 to lyse red blood cells.Interestingly, when the concentration of zinc ions is increased evenfurther (to up to 0.38%) by the incorporation of both zinc gluconate andzinc acetate into the gel, the lytic activity of nonoxynol-9 ismaintained. This finding further demonstrates the advantages ofcombinations of zinc salts over single zinc salts.

TABLE 4 Effect of Zinc Salts on the Detergent Actions of Nonoxynol-9Zinc Salt Percentage of Formulation of Gel Zinc Ions Lysis NegativeControl — − (lubricant base only) Positive Control — + (lubricant baseplus 8% nonoxynol-9) 0.8% zinc acetate 0.28 − 0.4% zinc acetate 0.14 +2% zinc gluconate 0.24 + 2% zinc gluconate + 0.24 + 0.14 (0.38) + 0.4%zinc acetate 1% zinc gluconate + 0.12 + 0.14 (0.26) + 0.4% zinc acetate1% zinc gluconate + 0.12 + 0.07 (0.19) + 0.2% zinc acetate 0.3% zincgluconate + 0.045 + 0.07 + 0.05 (0.165) + 0.2% zinc acetate + 0.2% zinclactate 0.3% zinc gluconate + 0.045 + 0.07 + 0.00 (0.115) + 0.2% zincacetate + 0.2% zinc citrate

The above-described studies suggest that zinc salts may be added tononoxynol-9-containing lubricants without impairing the detergentactivities of the nonoxynol-9. However, the assay of nonoxynol-9-inducedlysis employed in these studies was not quantitative. A second study wastherefore performed to quantify the effects of the addition of zincsalts on the detergent action of nonoxynol-9.

In these studies, 0.5 ml of lubricant (0.5 ml of PBS in the case ofcontrol) is added to 0.5 ml of packed red blood cells. After a fiveminute incubation at room temperature, the mixture is diluted with 1 mlPBS, mixed and centrifuged. The supernatant (containing the lysed redcells) is diluted 1:100 with PBS. Red cell hemolysis is then quantifiedby measuring the absorbance of 450 mm wavelength light transmitted bythe lysed cell supernatant using a Spectronic-20 spectrophotometer. Thehigh amount of absorbance indicates that a high amount of hemolysis hasoccurred. A solution containing only PBS is used as a blank reference.

The following two lubricants were compared:

Lubricant 1 (Lubricant Base Only) Xanthum gum 0.3% Water 44.1% Propylene Glycol  55% Silicone DC225 0.3% Silicone DC1403 0.3%

Lubricant 2 (Lubricant Base plus Zinc Salts) Xanthum gum 0.3% Water43.6%  Zinc gluconate 0.3% Zinc acetate 0.1% Zinc lactate 0.1% PropyleneGlycol  60% Silicone DC225 0.3% Silicone DC 1403 0.3%

TABLE 5 Quantitation of the Effects of Zinc Salts on the DetergentAction of Nonoxynol-9 Optical Density Lubricant (O.D. 450) Control (RedCells + PBS) 0.22 Lubricant 1 + NN9 (9% w/w) 0.50 Lubricant 2 + NN9 (9%w/w) 0.44

Although the addition of zinc salts to the lubricant base exerted aslight effect on the ability of nonoxynol-9 to lyse red blood cells,this effect was not statistically significant. Thus, the zinc saltcomposition containing 0.3% zinc gluconate+0.1% zinc acetate+0.1% zinclactate does not interfere with the detergent action of NN9, and thesame or lower concentrations of zinc salts can be used as ananti-irritant in sexual lubricants and creams of lubricants containingantimicrobial/antiviral agents which are used to prevent STD.

5.5. Example 5 Evaluation of the Effects of Zinc Salts on theAntimicrobial Action of Chlorhexidine Gluconate

Chlorhexidine gluconate is a microbicidal agent commonly used inantiseptic gels and creams employed in wound dressing. However, thisagent is known to cause irritation in at least some proportion of thehuman population. Zinc salts may be incorporated intochlorhexidine-containing products to prevent this irritation, but theymay also prevent the desired microbicidal effects of this compound.Thus, a series of studies were initiated to examine whether zinc saltsinterfered with the microbicidal effects of chlorhexidine.

In these studies, the ability of chlorhexidine to inhibit the growth ofS. aureus in culture was employed as an indicator of chlorhexidine'smicrobicidal effects. Briefly, 0.5 ml of a solution containing 1%chlorhexidine gluconate (CHG), 50% ethanol and 50% propylene glycol,plus or minus 2% zinc gluconate, was spread on the surface of a 3 cm×3cm piece of wound dressing. After drying for one hr, the dressing wassubdivided into 1 cm×1 cm pieces and placed on the surface of aTrypticase Soya Agar (TSA) plate seeded with 0.3 ml of S. aureus (10⁸colony-forming units (cfu)/ml) The plates were incubated at 37° C. for24 hr and the zone of inhibition was measured. The results of thesestudies are shown below in Table 5. The addition of 2% zinc gluconatehad no effect on the ability of chlorhexidine to inhibit the growth ofS. aureus, indicating that the addition of this concentration of zinc toa gel containing this microbicidal agent did not result in itsinactivation.

TABLE 6 Effect of Zinc on the Microbicidal Action of Chlorhexidine Zoneof Treatment inhibition (mm) Blank (no solution) 0 Negative Control (CHGsolution without zinc) 14 CHG solution + 2% zinc gluconate 17

5.6. Example 6 Hydroalcoholic Gel Formulations Containing Zinc SaltComplexes

The following alcohol gel formulations containing anti-irritant zincsalt complexes were prepared and some were then evaluated for theirrapid and sustained disinfectant activity either in vitro or in twovolunteers who have shown irritation and redness following exposure tocertain alcohol gels (Prevacare™, Johnson & Johnson).

(% By weight) ZINC GEL A Water 26.63 Ucare (JR 30) 0.3 Zinc gluconate0.3 Zinc acetate 0.1 Zinc lactate 0.1 Germall plus 0.2 Chlorhexidinegluconate 0.05 Benzalkonium chloride 0.12 Ethanol 70 Phenoxyethanol 0.7Glycerin 1.0 Cetyl ether (PPG 10) 0.5 ZINC GEL B Water 26.13 Ucare (JR30) 0.3 Zinc gluconate 0.3 Zinc acetate 0.1 Zinc lactate 0.1 Germallplus 0.2 Chlorhexidine gluconate 0.05 Benzalkonium chloride 0.12 Ethanol70 Phenoxyethanol 0.7 Glycerin 1.0 Cetyl ether (PPG 10) 0.5 Vitamin C0.5 ZINC GEL C Water 25.53 Ucare (JR 30) 0.3 Zinc gluconate 0.3 Zincacetate 0.1 Zinc lactate 0.1 Germall plus 0.2 Chlorhexidine gluconate0.05 Benzalkonium chloride 0.12 Ethanol 70 Klucel 0.3 Phenoxyethanol 0.7Glycerin 1.0 Cetyl ether (PPG 10) 0.5 Triclosan 0.3 Vitamin C (Ascorbicacid) 0.5 ZINC GEL D Water 26.13 Ucare (JR-30) 0.2 Zinc gluconate 0.3Zinc acetate 0.1 Zinc lactate 0.1 Germall plus 0.2 Chlorhexidinegluconate 0.05 Benzalkonium chloride 0.12 Ethanol 70 Incroquat 0.6Phenoxyethanol 0.7 Glycerin 1.0 ZINC GEL D1 Water 26.73 Ucare (JR-30)0.2 Zinc gluconate 0.3 Zinc acetate 0.1 Zinc lactate 0.1 Germall plus0.2 Chlorhexidine gluconate 0.05 Benzalkonium chloride 0.12 Ethanol 70Phenoxyethanol 0.7 Glycerin 1.0 Cetyl ether (PPG 10) 0.5 ZINC GEL EWater 25.33 Ucare (JR 30) 0.2 Zinc gluconate 0.3 Zinc acetate 0.1 Zinclactate 0.1 Germall plus 0.2 Chlorhexidine gluconate 0.05 Benzalkoniumchloride 0.12 Ethanol 70 Incroquat 0.6 Phenoxyethanol 0.7 Glycerin 1.0Cetyl ether (PPG 10) 0.5 Triclosan 0.3 Vitamin C 0.5 ZINC GEL F Water26.08 Ucare (JR30) 0.2 Zinc gluconate 0.1 Zinc acetate 0.1 Zinc lactate0.05 Germall plus 0.2 Chlorhexidine gluconate 0.05 Benzalkonium chloride0.12 Ethanol 70 Incroquat 0.6 Phenoxyethanol 0.7 Glycerin 1.0 Cetylethyl (PPG10) 0.5 Incromide CAC 0.3 ZINC GEL G Water 26.55 Ucare (JR30)0.2 Zinc gluconate 0.1 Zinc acetate 0.1 Zinc lactate 0.05 Germall plus0.2 Ethanol 70 Incroquat 0.6 Phenoxyethanol 0.7 Glycerin 1.0 Cetyl ethyl(PPG10) 0.5

Rapidity Of Action In Vitro. To test for rapid activity, 0.2 ml of 10⁹cfu/ml of bacterial culture or 10⁶ cfu/ml of fungal culture (diluted 1:1with bovine adult serum) was placed in a sterile culture tube and 0.8 mlof the zinc gel was added and mixed. After 15 seconds, the antimicrobialactivity was stopped with LTSB (Lecithin-containing Trypticase SoyaBroth; a drug-inactivating media) and an aliquot was subcultured on aTSA (Trypticase Soya Agar) plate. The plates were then incubated for 24hours at 37° C. to determine the number of microbial colonies per tube.Phosphate buffered saline was used instead of gel for the control. Asshown in Table 7, no active bacteria or fungi could be recovered fromany of the tubes 15 seconds after the addition of zinc gels A, D and G.In contrast, nearly all of the bacteria or fungi could be recovered fromthe tubes to which PBS was added.

TABLE 7 The Rapid Disinfectant Actions of Hydroalcoholic Gels ContainingZinc Salts Zinc Gel Zinc Gel Zinc Gel A D G Control Organism (cfu/tube)(cfu/tube) (cfu/tube) (cfu/tube) S. aureus 0 0 0 1.1 × 10⁷ S. epidermis0 0 0 1.0 × 10⁷ S. aureus 0 0 0 7.3 × 10⁶ (methicillin resistant) K.pneumoniae 0 0 0 3.0 × 10⁷ E. coli 0 0 0 2.3 × 10⁶ C. albicans 0 0 0 1.5× 10⁵

Sustainability of Disinfectant Action In Vitro. Hides from freshlykilled pigs were obtained from a slaughter house. The skin was washedwith water, dehaired and defatted using scalpel. It was then cut intosmaller sections, rinsed with water and preserved in sealed plastic bagsin a freezer. Before use, a section was removed, thawed and rinsed inwater and cut into pieces (3×3 cm) with a blade. These skin pieces weremounted on holders (plastic plates of 5 cm diameter) with epoxy toexpose the skin surface. Two pieces of skin were used per sample. 0.3 mlof the test formulation was applied on one piece and rubbed on otherpiece from a matched pair for 30 sec. After 15 min, one of the twopieces was inoculated with 30 μl of a S. aureus culture (10⁷ cfu/ml).The two matching skin pieces were rubbed together for 15 sec. After 30sec, each skin piece was rinsed with LTSB to recover viable organismsand an aliquot from this LTSB wash was subcultured on a D/E plate toquantitate the surviving organisms. Zinc gel without any antiseptic wasused as control. As shown in Table 8, Prevacare™ and Avagard™ killedapproximately 50% and 90%, respectively, of the bacteria inoculated onthe pig skin 15 minutes after their application. In contrast, more than99.9% of all inoculated bacteria were killed when applied to pig skin 15minutes after treatment with Zinc gels D or E. These findings indicatethat these zinc gels retain their full potency as disinfectants for atleast 15 minutes after their use, and therefore are superior to theexisting hydroalcoholic gel disinfectants Prevacare™ and Avagard™.

TABLE 8 The Sustainability of the Disinfectant Actions of HydroalcoholicGels Containing Zinc Salts Formulation cfu/test Control 3.0 × 10⁵ ZincGel D 48 Zinc Gel E 3 Prevacare ™ 1.5 × 10⁵ Avagard ™ 3.9 × 10⁴

Hydroalcoholic Zinc Gels Fail to Irritate the Skin of IndividualsSensitive to Other Hydroalcoholic Gels. Two volunteers who hadpreviously exhibited sensitivity to the hydroalcoholic gel Prevacare™were enlisted for this study. Two gm of Prevacare™ or the zinc gelindicated in Table 9 was applied to the palm and spread all over thehands. Skin reactions were observed after 15 minutes of exposure to thegel. The results of these studies are shown in Table 9.

TABLE 9 Hydroalcoholic Zinc Gels Are Not Irritating To individuals WhoExhibit Sensitivity to Prevacare ™. Volunteer Prevacare ™ Zinc Gel AZinc Gel E 1 Redness None None 2 Redness and Itching None None

In an unrelated study of the antimicrobial efficacy of Avagard™, it wasalso noted that this hydroalcoholic gel also caused skin irritation insome individuals. Thus, the above findings may be of generalsignificance to the prevention of skin irritation induced byalcohol-based disinfectant products.

5.7. Example 7 Evaluation of the Effects of Zinc Salts on the Preventionof Latex-induced Contact Dermatitis

Latex gloves are known to cause contact dermatitis in some individuals.Latex-induced contact dermatitis is an especially serious concern amongsurgeons and other health care workers who face unavoidable exposure tolatex in surgical gloves and other medical devices. The following threezinc gel surgical hand preps may be useful in protecting against thisproblem.

(% by wt) ZINC GEL SURGICAL HAND PREP-1 Water 33.13 Ucare (JR30) 0.2Zinc gluconate 0.5 Zinc acetate 0.1 Zinc lactate 0.1 Germall plus 0.2Chlorhexidine gluconate 0.05 Benzalkonium chloride 0.12 Ethanol 60Incroquat 0.6 Polawax 0.5 Zinc stearate 2.0 Phenoxyethanol 0.7 Glycerin1.0 Cetyl ether (PPG10) 0.5 Silicone DC1403 0.3 ZINC GEL SURGICAL HANDPREP-2 Water 30.03 Ucare (JR30) 0.2 Zinc gluconate 0.5 Zinc acetate 0.1Zinc lactate 0.1 Germall plus 0.2 Chlorhexidine gluconate 0.05Benzalkonium chloride 0.12 Ethanol 63 Incroquat TMS 0.6 Polawax 0.3Stearyl alcohol 0.3 Zinc stearate 2.0 Phenoxyethanol 0.7 Glycerin 1.0Cetyl ether (PPG10) 0.5 Silicone DC1403 0.3 ZINC GEL SURGICAL HANDPREP-3 Water 29.13 Ucare (JR30) 0.2 Zinc gluconate 0.5 Zinc acetate 0.1Zinc lactate 0.1 Germall plus 0.2 Chlorhexidine gluconate 0.05Benzalkonium chloride 0.12 Ethanol 65 Incroquat 0.6 Polawax 0.5 Zincstearate 1.0 Phenoxyethanol 0.7 Glycerin 1.0 Cetyl ether (PPG10) 0.5Silicone DC1403 0.3

The efficacy of zinc gel surgical hand prep-1 was tested on a volunteerknown to develop contact dermatitis when in contact with latex gloves.In this study, the volunteer donned latex gloves and carried out normalactivities. After 30 min, redness and irritation was observed on theback or the palm of the hand. Later that same day, after the redness andirritation subsided, the volunteer applied 2 g of the zinc surgical handprep and, after the alcohol evaporated off, donned latex gloves. Noreaction was seen when the gloves were removed after 2 hours. Thesefindings confirm the potential utility of zinc-containing gels toprevent latex-induced contact dermatitis.

5.8. Example 8 The Incorporation of Zinc Salts into Alcohol Gel WipesPrevents the Irritating Effects of Alcohol While MaintainingDisinfectant Efficacy

Individually sealed alcohol-impregnated wipes are useful for thedisinfection of topical and various other physical surfaces. Whenapplied topically, however, the alcohol from the wipe may sometimescause skin irritation. Thus, the addition of zinc salt formulations toalcohol gel wipes is useful in preventing alcohol-induced skinirritation. One such zinc-containing alcohol gel wipe for handdisinfection is composed of the following:

ZINC GEL X SOLUTION (% By weight) Water 20.93 Ucare (JR 30) 0.2 Zincgluconate 0.3 Zinc acetate 0.1 Zinc lactate 0.1 Germall plus 0.2Chlorhexidine gluconate 0.05 Benzalkonium chloride 0.12 Ethanol 75Incroquat 0.6 Polawax 0.2 Phenoxyethanol 0.7 Glycerin 1.0 Cetyl ether(PPG 10) 0.5Five ml of this solution is dispensed onto each wipe and the wipes arepacked in plastic lined bags and sealed for future use as aids indisinfection.

5.9. Example 9 The Incorporation of Zinc Salts into Gels and Creams toPotentiate their Anti-itch Properties

Various gels and creams are known in the art for their abilities totreat itchiness or psoriasis. However, some of the ingredients containedin these products may in fact cause irritation in the very individualsthey are intended to treat. The incorporation of zinc salt formulationsto these products will prevent their irritating properties whileretaining their therapeutic effects.

A triple zinc anti-itch aqueous cream or lotion is composed of thefollowing:

TRIPLE ZINC ANTI-ITCH LOTION (% by wt) Incroquat TMS 0.8 Polawax NF 0.8Petroleum Jelly 3.0 Crothix 1.0 Crodomol MM 1.0 Cremerol 1.0 Propyleneglycol 2.0 Glycerin 8.0 Water 77.3 Ucare JR30 0.2 Germall plus 0.2 Zincgluconate 1.0 Zinc acetate 0.1 Zinc lactate 0.1 Zinc stearate 3.0 Zincoxide 0.5

A triple zinc cream for the treatment of psoriasis is composed of thefollowing:

TRIPLE ZINC CREAM FOR TREATING PSORIASIS (% by wt) Petroleum Jelly 25Incroquat 1.0 Polawax NF 1.0 Glycerin 10.0 Propylene Glycol 10.0 Crothix2.0 Zinc oxide 3.0 Zinc stearate 3.0 Allatoin 0.5 Salicylic acid 2.0Dimethicone 2.0 Water 38.8 Zinc gluconate 1.0 Zinc acetate 0.1 Zinclactate 0.1 Germall plus 0.2 Chlorhexidine gluconate 0.05 Benzalkoniumchloride 0.05 Ucare JR 30 0.2

To treat itchiness or psoriasis, a therapeutically effective amount ofthe triple zinc anti-itch lotion or the triple zinc cream for treatingpsoriasis is applied to the area to be treated as necessary to maintainthe skin surface free or itchiness or the symptoms of psoriasis.

5.10. Example 10 The Incorporation of Zinc Salts into Antimicrobial GelsContaining Chlorhexidine Gluconate and Benzalkonium Chloride does notReduce Their Antimicrobial Efficacy

The antimicrobial agents chlorhexidine gluconate and benzalkoniumchloride are known in the art as preservatives in various products. Whatwas not previously appreciated in the art, however, was that theaddition of incroquat significantly potentiates the preservative effectsof chlorhexidine gluconate and benzalkonium chloride. To demonstratethis synergism between incroquat and chlorhexidine gluconate andbenzalkonium chloride, gels with or without chlorhexidine gluconate andbenzalkonium chloride or with or without incroquat were examined for therapidity with which they could kill bacteria in culture. In thesestudies, 1 ml of 10⁸ cfu of S. aureus was mixed with 1.0 ml of BovineAdult Serum (BAS) and 1.0 ml of the one of the gels indicated below inTable 10. After 15 seconds, a 0.5 ml aliquot was removed and added to4.5 ml of the drug inactivating media LTSB. The resulting mixture wasthen diluted 100 fold with LTSB. After mixing, a 0.5 ml aliquot of thediluent was plated on TSA plates, which then were incubated at 37° C.for 24 hours to determine the colony counts.

TABLE 10 Compositions of Gels Containing Various Combinations ofChlorhexidine Gluconate and Benzalkonium Chloride and Incroquat. Gel GelGel Gel Gel Gel Ingredients #1 #2 #3 #4 #5 #6 Water 33.3 33.125 33.032.825 32.525 32.25 U care (JR30) 0.2 0.2 0.2 0.2 0.2 0.2 Ethanol 65 6565 65 65 65 Glycerin 1.0 1.0 1.0 1.0 1.0 1.0 Cetylether PPG10) 0.5 0.50.5 0.5 0.5 0.5 CHG — 0.05 — 0.05 0.05 0.05 BZK — 0.125 — 0.125 0.1250.125 Incroquat — — 0.3 0.3 0.6 0.6 Zinc gluconate — — — — — 0.15 Zincacetate — — — — — 0.1 Zinc lactate — — — — — 0.05

As shown in Table 11, the addition of chlorhexidine gluconate andbenzalkonium chloride to the gel base (Gel #2) resulted in a ten-foldreduction in the amount of bacteria recovered over that observed withthe gel base alone. The addition of incroquat alone to the gel base (Gel#3) only mildly affected the numbers of bacteria that could be recoveredat 24 hrs after the addition of the gel to the bacterial culture.However, the addition of chlorhexidine gluconate, benzalkonium chlorideand incroquat to the gel base (Gel #4) resulted in a 4-log reduction inthe amount of bacteria that could be recovered from the culture. Thus,there is a high degree of synergy between the antibacterial effects ofchlorhexidine gluconate and benzalkonium chloride and incroquat.

TABLE 11 The Addition of Incroquat Synergistically Potentiates theAntimicrobial Effects of Gels Containing Chlorhexidine Gluconate andBenzalkonium Chloride Bacterial Growth Fold reduction Gel (cfu/tube)over control 1 3.0 × 10⁷ — 2 3.0 × 10⁶ 1.0 3 1.6 × 10⁷ 0.48 4 3.0 × 10³4.0

Having established the strong synergy between chlorhexidine gluconate,benzalkonium chloride and incroquat, it was important to determinewhether the further addition of potentially non-irritating zinc salts tothis gel would abolish the antimicrobial effects. Thus, the consequencesof the addition of zinc salts to gels with chlorhexidine gluconate,benzalkonium chloride and incroquat on their sustained anti-bacterialactivity were evaluated using the pig skin model described above inSection 5.6. The results of these studies, shown in Table 12,demonstrate that the addition of zinc (Gel #6) did not interfere withthe strong antimicrobial effect seen in gels containing chlorhexidinegluconate, benzalkonium chloride and incroquat (Gel #5) over those seenin gels containing only chlorhexidine gluconate and benzalkoniumchloride (Gel #2) or the gel base alone (Gel #1). Thus, zinc salts maybe added to antimicrobial gels containing chlorhexidine gluconate,benzalkonium chloride and incroquat to prevent their potentialirritation without compromising their antimicrobial effects.

TABLE 12 The Antimicrobial Synergism Observed in Gels ContainingChlorhexidine Gluconate, Benzalkonium Chloride and Incroquat isMaintained in the Presence of Zinc Salts Bacterial Growth GelFormulation (cfu/test) Gel #1 1.8 × 10⁵ Gel #2 4.1 × 10⁴ Gel #5 2.0 ×10² Gel #6 1.0 × 10²

This finding of synergistic antimicrobial activity between chlorhexidinegluconate, benzalkonium chloride and incroquat in the presence of zincsalts was also observed in alcohol-based gels. For example, as shown inTable 13, a 4-log reduction in bacterial growth was observed in analcohol-based zinc hydrogel containing chlorhexidine gluconate,benzalkonium chloride and incroquat (gel D; see Section 5.6), ascompared to the only 2-log reduction in bacterial growth observed withzinc gel D1 (see Section 5.6), which containing chlorhexidine gluconateand benzalkonium chloride but lacked incroquat. These findings confirmthat the addition of incroquat significantly potentiates thepreservative effects of chlorhexidine gluconate and benzalkoniumchloride, and that these preservative effects are not abolished by thepresence of zinc salts within the gel.

TABLE 13 The Addition of Incroquat Potentiates the Antimicrobial Effectsof Zinc Gels Containing Chlorhexidine Gluconate and BenzalkoniumChloride Bacterial Growth Gel Formulation (cfu/test) Control Base* 4.0 ×10⁵ Zinc Gel D1 2.0 × 10³ Zinc Gel D   1 × 10² Prevacare 1.5 × 10⁵*Control base is same as D1 except does not contain Germall plus,chlorhexidine gluconate, benzalkonium chloride and phenoxyethanol.

Synergistic potentiation of antimicrobial activity is also observed ingels containing chlorhexidine gluconate, benzalkonium chloride,incroquat and Sensiva® (octoxyglycerin). Thus, additional studies wereperformed to establish that the synergistic antimicrobial effects ofthese compounds was not abolished by the addition of zinc salts to gelscontaining these ingredients. The compositions of the gels tested areshown in Table 14. The studies were performed using the pig skin modeldescribed above in Section 5.6. As shown in Table 15, the addition ofzinc (Gel #3) did not interfere with the strong antimicrobial effectseen in gels containing chlorhexidine gluconate, benzalkonium chloride,incroquat and Sensiva® (Gel #2) over those seen in gels containing onlySensiva®& (Gel #5), incroquat (Gel #4), Sensiva® plus incroquat (Gel#6), chlorhexidine gluconate, benzalkonium chloride, and Sensiva® (Gel#1) or the gel base alone (Gel #7). Thus, zinc salts may be added toantimicrobial gels containing chlorhexidine gluconate, benzalkoniumchloride, incroquat and Sensiva® to prevent their potential irritationwithout compromising their antimicrobial effects.

TABLE 14 Compositions of Gels Containing Various Combinations ofChlorhexidine Gluconate, Benzalkonium Chloride, Incroquat and Sensiva ®.Gel Gel Gel Gel Gel Gel Gel Ingredients #1 #2 #3 #4 #5 #6 #7 Water32.125 31.525 31.225 32.7 32.3 32.9 33.3 Ucare 0.2 0.2 0.2 0.2 0.2 0.20.2 Ethanol 65 65 65 65 65 65 65 Glycerin 1.0 1.0 1.0 1.0 1.0 1.0 1.0Cetylether PPG10 0.5 0.5 0.5 0.5 0.5 0.5 0.5 CHG 0.05 0.05 0.05 — — — —BZK 0.125 0.125 0.125 — — — — Sensiva ® 1.0 1.0 1.0 — 1.0 1.0 —Incroquat — 0.6 0.6 0.6 — 0.6 — Zinc gluconate — — 0.15 — — — — Zincacetate — — 0.1 — — — — Zinc lactate — — 0.05 — — — —

TABLE 15 The Antimicrobial Synergism Observed in Gels ContainingChlorhexidine Gluconate, Benzalkonium Chloride, Incroquat and Sensiva ®is Maintained in the Presence of Zinc Salts Bacterial Growth GelFormulation (cfu/test) Gel #1 7.9 × 10² Gel #2 3.0 × 10¹ Gel #3 2.0 ×10¹ Gel #4 1.6 × 10⁵ Gel #5 2.9 × 10⁴ Gel #6 3.0 × 10³ Gel #7 3.0 × 10⁵

5.11. Example 11 The Incorporation of Zinc Salts into HydroalcoholicGels Containing 1.0% Chlorhexidine Prevents the Irritating Effects ofAlcohol and Chlorhexidine While Maintaining Disinfectant Efficacy

Latex gloves are beneficial in minimizing or preventing transmission ofvarious infectious agents, but an increasing proportion of thepopulation is developing an allergic reaction to latex that results inthe development of contact dermatitis. Because zinc salts can preventthe irritation caused by latex, the addition of zinc salts tohydroalcoholic gels or creams to be applied to the skin underneath theglove will be useful in preventing this latex-induced contactdermatitis. Furthermore, if the hydroalcoholic gels also comprise 1.0%chlorhexidine, the barrier to the transmission of infectious agents willbe further improved provided that the zinc salts do not inactivate theantimicrobial effects of the chlorhexidine. The following formulationtherefore will be useful as a topical disinfectant to be applied to skinsubsequently covered by latex articles.

HYDROALCOHOLIC ZINC GEL CONTAINING 1.0% CHLORHEXIDINE FOR LONG TERMACTIVITY (% by wt) Water 25.25 Ucare (JR 30) 0.15Hydroxypropylmethylcellulose (K-100) 0.15 Germall plus 0.2 Zincgluconate 1.0 Zinc acetate 0.2 Zinc lactate 0.1 Chlorhexidine gluconate(20%) 5.0 Benzalkonium chloride (50%) 0.25 Ethanol 60 Incroquat 0.7Polawax 0.3 Phenoxyethanol 0.7 Glycerin 2.0 Cetylether (PPG 10) 1.0Vitamin E 0.2 Zinc stearate 3.0

The efficacy of the gel described immediately above was tested on avolunteer known to develop contact dermatitis when in contact with latexgloves. In this study, the volunteer applied 2 g of the hydroalcoholiczinc gel containing 1.0% chlorhexidine and, after the alcohol evaporatedoff, donned latex gloves and carried out normal activities. No reactionwas seen when the gloves were removed after 3 hours. These findingsconfirm the potential utility of zinc-containing gels to preventlatex-induced contact dermatitis.

5.12. Example 12 Topical Creams Containing Triple Zinc Salts ProtectAgainst Dermal Irritation Caused by Various Physical, Chemical,Mechanical or Biological Irritants

A topical triple zinc anti-itch cream or lotion of the followingcomposition was prepared:

TRIPLE ZINC ANTI-ITCH LOTION (% by wt) Incroquat TMS Behenyl 0.8 PolawaxNF 0.8 Petroleum Jelly 3.0 Crothix 1.0 Crodomol MM 1.0 Cremerol HMG 1.0Propylene glycol 2.0 Glycerin 8.0 Water 77.3 UCare JR30-M 0.2 Germallplus 0.2 Zinc gluconate 0.3 Zinc acetate 0.1 Zinc lactate 0.1 Zincstearate 3.0 Zinc oxide 0.5

The topical triple zinc anti-itch lotion then was tested on volunteersto determine whether it could protect against the skin irritationresulting from dryness (e.g. winter itch), prickly heat, mechanicalinsult (e.g. shaving or abrasive procedures), contact with poison ivy,diaper rash, contact with detergents such as sodium lauryl sulfate,nonoxinol-9, chemical agents, antimicrobial agents, alcohol, etc. Theresults of these studies are described in Table 16.

TABLE 16 Evaluation of Topical Triple Zinc Anti-itch Lotion inPrevention of Skin Irritation Caused by Physical, Chemical, Mechanicalor Biological Irritants Number of Time after application volunteersrequired for cessation of Problem/Irritant tested irritation/woundhealing Winter itch* 4 10–15 minutes Prickly heat 1 15–20 minutes Skinirritation 2 5–10 minutes after shaving Poison ivy 2 10–15 minutespsoriasis itch 2 10–20 minutes scratch wound 1 2 days *Two of the fourvolunteers tried the same lotion without zinc gluconate, zinc acetateand zinc lactate, but the irritation ceased only after severalapplications.

Based on these observations, this triple zinc anti-itch lotion reducesthe skin irritation produced by a wide range of irritants, includingthose of physical, chemical, biological, or mechanical origins.

5.13. Example 13 Topical Creams Containing Triple Zinc Salts ProtectAgainst Dermal Irritation Caused by Essential Oils (EO) and Fragranceand Flavor (FF) Chemicals

Essential oils are volatile oils obtained from plant or animal sourcesand are composed of complex mixtures of several constituents asmonoterpenes and sesquiterpene hydrocarbons, monoterpene andsesquiterpene alcohols, esters, ethers, aldehydes, ketones, oxides andthe like. These essential oils and their isolated constituents have beenmainly used as fragrance and flavor agents in several formulations.These essential oils have also been known to show antimicrobial,anti-inflammatory and wound-healing properties.

However, there have been several reports about the skin-sensitizingeffect of these essential oils. The spectrum of reported skin reactionsto essential oils includes contact dermatitis, irritant contactdermatitis, phototoxic reactions and urticaria. See De Groot A, Frosch PJ. Adverse reactions to fragrances: a clinical review. ContactDermatitis 1997;36:57-86. A mixture of almond, ylang-ylang, neroli,sandalwood and frankincense oils was shown to have resulted in apositive patch-test on a patient whose skin was exposed to the mixtureof these oils. See Bleasel N, Tate B and Rademaker M. Allergic contactdermatitis following exposure to essential oils. Australian Journal ofDermatology 2002;43:211-213. Repeated intradermal dosing with peppermintoil was reported to have produced moderate and severe reactions inrabbits. See Nair B. Final report on the safety assessment of MenthaPiperita (Peppermint) oil, Mentha Piperita (Peppermint) Leaf extract,Mentha Piperita (Peppermint) leaf and Mentha Piperita (Peppermint)water. International Journal of Toxicology 2001 ;20(Suppl 3):61-73.

Researchers have also shown that lavender oil is responsible for contactdermatitis using the patch testing method, which was carried out for aperiod of 9 years. See Sugiura M, Hayakawa R, Kato Y, Sugiura K,Hashimoto R. Results of patch testing with lavender oils in Japan,Contact Dermatitis 2000;43:157-160. Jasmine absolute, geranium oilbourbon, spearmint oil, clove oil, lemongrass oil and cedarwood oil alsohave been shown to produce allergic contact dermatitis. See generallyLarsen W, Nakayama H, Fischer T, Elsner P, Frosch P, Burrows D, JordanW, Shaw S, Wilkinson J, Marks J Jr, Sugawara M, Nethercott M, NethercottJ. Fragrance contact dermatitis: a worldwide multicenter investigation(Part II). Contact Dermatitis 2001;44:344-346; and Wohrl S, Hemmer W,Focke M, Gotz M, Jarisch R. The significance of fragrance mix, balsam ofPeru, colophony and propolis as screening tools in the detection offragrance allergy. British Journal of Dermatology 2001;145(2):268-273.There has been a recent report that a girl who was using a fragrancecontaining the essential oil of tangerine, suffered from itchingerythema and papules on areas of contact on the hands, face and neck.See Vilaplana J, Romaguera C. Contact dermatitis from the essential oilof tangerine in fragrances. Contact Dermatitis 2002;46:108.

Apart from the essential oils, their individual ingredients, eitherisolated from the oil or chemically synthesized have also been show tohave skin sensitizing effect. L-citronellol, α-amylcinnamaldehyde andlyral have been shown to test positive to skin sensitization tests. SeeLarsen W, Nakayama H, Fischer T, Elsner P, Frosch P, Burrows D, JordanW, Shaw S, Wilkinson J, Marks J Jr, Sugawara M, Nethercott M, NethercottJ. Fragrance contact dermatitis: a worldwide multicenter investigation(Part II). Contact Dermatitis 2001 ;44:344-346. Geraniol, farnesol,hydroxycitronellal, isoeugenol, and eugenol have also been reported totest positive to skin patch-tests See Larsen W, Nakayama H, Fischer T,Elsner P, Frosch P, Burrows D, Jordan W, Shaw S, Wilkinson J, Marks JJr, Sugawara M, Nethercott M, Nethercott J. Fragrance contactdermatitis: a worldwide multicenter investigation (Part II). ContactDermatitis 2001;44:344-346 and Wohrl S, Hemmer W, Focke M, Gotz M,Jarisch R. The significance of fragrance mix, balsam of Peru, colophonyand propolis as screening tools in the detection of fragrance allergy.British Journal of Dermatology 2001;145(2):268-273. Eucalyptol was shownto result in the appearance of pruritus and erythema on the skin of anathlete, who was using a cream containing eucalyptol. See Vilaplana J,Romaguera C. Contact dermatitis from the essential oil of tangerine infragrances. Contact Dermatitis 2002;46:108.

In order to incorporate essential oils, their isolated ingredients andother natural or synthetic fragrance and flavor chemicals in topicalformulations without causing contact dermatitis, the following topicalformulations containing the triple zinc salts with and without essentialoils (EO) and fragrance and flavor chemicals (FF) were prepared inaqueous and alcohol base:

Alcohol Zinc Fel Hand Wash #1

Ingredient % by weight UCare JR30-M 0.05 Methocel K100 0.1 Water 36.08Zinc gluconate 0.3 Zinc acetate 0.1 Zinc lactate 0.1 Germall Plus 0.2Ethanol 58 Ispropanol 2.0 Silicone (Dimethicone) 0.2 Incroquat BehentylTMS 0.7 Polawax A31 0.3 Glycerin 1.0 Cetyl ether (PPG10) 0.5 CHG 0.05BZK 0.02 Farnesol 0.3

Alcohol Zinc Gel for use Under Latex Glove

Ingredients % by weight Ucare JR30-M 0.8 Methocel K100 0.3 Water 27.13Zinc gluconate 0.6 Zinc acetate 0.2 Zinc lactate 0.2 Germall Plus 0.2Zinc stearate 1.5 Zinc oxide 1.0 Glucate DO 5.0 Ethanol 55.0 Ispropanol3.0 Silicone (Dimethicone) 0.5 Incroquat Behenyl TMS 1.0 Polawax A31 0.5Glycerin 2.0 Cetyl ether (PPG10) 1.0 CHG 0.05 BZK 0.02 Farnesol 0.3Vitamin E 0.2

Triple Zinc Anti-itch Lotion with EO and FF Ingredients

Ingredients (% by wt) Incroquat Behenyl TMS 0.8 Polawax NF 0.8 PetroleumJelly 3.0 Crothix 1.0 Crodomol MM 1.0 Cremerol 1.0 Propylene glycol 2.0Glycerin 8.0 Water 77.4 Ucare JR30 0.2 Germall + 0.2 Zinc gluconate 0.3Zinc acetate 0.1 Zinc lactate 0.1 Zinc stearate 3.0 Zinc oxide 0.5Farnesol 0.3 Lemon oil 0.3

Anti-irritant Disinfectant Soap with EO AND FF Ingredients

Ingredients % By weight Polyox WSR 205 0.1 UCare Jr30-M 0.2 Germall Plus0.2 Water 86.93 Pluronic F87 2.0 Cocoamidopropylbetaine 1.0 Mirapol A-151.0 Propylene glycol 2.0 Polyquaternium-47(Merquat 3330) 3.0 Glycerin2.0 CHG 0.05 BZK 0.12 Triclosan 0.3 Farnesol 0.3 Lemon oil 0.3 Zincacetate 0.1 Zinc lactate 0.1 Zinc gluconate 0.3

5.14. Example 14 Anti-irritant Antimicrobial Compositions ContainingZinc Salts and Panthenol Protect Against Dermal Irritation

Although anti-irritant compositions containing two or more soluble zincsalts such as those described above can reduce skin irritation,hydroalcoholic formulations containing zinc salts at concentrationsabove 0.5% may be unstable, due either to interaction between zinc saltswith other ingredients or to insolubility of the zinc salts in thealcohol. However, when lower concentration of zinc salts are used(0.1%-0.5%), the stability of the formula may be improved at the expenseof its anti-irritant properties.

D,L panthenol is used as a deep penetrating moisturizer and is reportedto have wound healing and anti-inflammatory effects when used in topicalformulations. The effects of the addition of panthenol toantimicrobial/anti-irritant compositions containing zinc salts wereevaluated. In these studies, the following compositions were generatedand analyzed for their ability to reduce or prevent the potentiallyirritating effects of antiperspirants or aftershave lotions:

Stock solutions: Ingredients % (wt/wt) (1) Gel with panthenol Water 88.0U-care JR 30M 2.0 D,L Panthenol 50W (50% in water) 10.0 (2) Gel withsoluble zinc salts Water 95.0 U-care JR 30M 2.0 Zinc acetate 1.0 Zincgluconate 1.0 Zinc lactate 1.0 (3) Gel with only zinc salts + panthenolwater 85.0 U-care JR 30M 2.0 Zinc Acetate 1.0 Zinc lactate 1.0 Zincgluconate 1.0 D,L Panthenol 50W 10.0 (4) Gel with soluble and insolubleorganic zinc salts Water 90.0 U-care JR 30M 2.0 Zinc acetate 1.0 Zincgluconate 1.0 Zinc lactate 1.0 Zinc stearate 5.0 (5) Gel with solubleand insoluble organic zinc salts + panthenol Water 80.0 U-care JR 30M2.0 Zinc Acetate 1.0 Zinc lactate 1.0 Zinc gluconate 1.0 Zinc stearate5.0 D,L Panthenol 50W 10.0 (1) A gel with only panthenol (2) A gel withonly soluble zinc salts (3) A gel with soluble zinc salts + panthenol(4) A gel with soluble zinc salts + insoluble zinc salts (5) A gel withsoluble zinc salts + insoluble zinc salts + panthenol

A volunteer who is sensitive to antiperspirant and alcohol-containingaftershave lotion was selected for the test. 10% of each of the gels wasincorporated into 90% of the antiperspirant. After showering, thevolunteer applied 1 g. of the gel on the under arm area of one side ofthe body and the control antiperspirant to the under arm area on theother side of the body. The reaction then was noted. This experiment wasrepeated with the other four gels on the next four consecutive days.

The results were quantified as follows. A severe response was given ascore of ‘3+,’ a moderate response a score of ‘2+,’ a mild response ascore of ‘1+,’ and no response a score of ‘0.’ The results of the studyare presented in Table 17.

TABLE 17 Gels containing zinc salts and panthenol prevented the stingingand itching associated with antiperspirants Stinging Itching Control  1+2+ Gel 1 0 2+ Gel 2 0 1+ Gel 3 0 0.5+  Gel 4 0 1+ Gel 5 0 0 

A similar study was performed using an alcohol-containing aftershavelotion. The lotion was prepared as follows:

Ingredients % (wt/wt) Ethanol 40.0 Water 58.8 U-care JR 30M 0.2 Glycerin1.0Gels 1, 2 and 3, which did not contain zinc stearate, then were mixedwith an alcohol-containing aftershave lotion, at a ratio of 10% gel:90%aftershave, and tested in the volunteer, who applied 0.5 g of thecontrol lotion to one side of the face and the same amount of the testlotion to the other side of the face immediately after shaving. Theother two lotions were tested similarly on each of the next twoconsecutive days.

The results of these studies are shown in Table 18. Scoring of theresponse was performed as described immediately above for theantiperspirant studies.

TABLE 18 Lotions containing zinc salts and panthenol prevented thestinging and irritation associated with alcohol-based aftershave lotionScoring Stinging Erythema Control Lotion 2+ 1+ Lotion with Gel 1(Panthenol) 2+ 1+ Lotion with Gel 2 (Zinc salts) 1+ 0.5+ Lotion with Gel3 (Zinc salts + Panthenol) 0 0

Anti-irritant compositions containing two or three soluble organic zincsalts (0.1-0.5%), D,L Panthenol (0.5-2%) and a cellulose polymer gellingagent (0.1-0.5%) also were prepared. The cellulose polymers studied werepolyquaternium-10 and hydroxy propyl methyl cellulose. The compositionswere as follows:

Ingredients %(wt/wt) Zinc Gel A Water 85.0 U-care JR30M 2.0 Zinc acetate1.0 Zinc lactate 1.0 Zinc gluconate 1.0 D,L Panthenol 50W 10.0 Zinc GelB Water 84.0 U-care JR30M 2.0 Zinc lactate 2.0 Zinc gluconate 2.0 D,LPanthenol 50W 10.0 Zinc Gel C Water 83.0 U-care JR 30M 2.0 Hydroxypropylmethyl 1.0 cellulose (Methocell K4MS) Zinc lactate 2.0 Zinc gluconate2.0 D,L Panthenol 50W 10.0 Zinc Gel D Water 79.0 U-care JR30 2.0 Zinclactate 2.0 Zinc gluconate 2.0 Zinc stearate 5.0 D,L Panthenol 50W 10.0These zinc gels also can be incorporated into antiperspirants,aftershave lotions, hydroalcoholic skin disinfectants, therapeuticcreams etc.

Anti-irritant zinc compositions containing two soluble organic zincsalts and panthenol were prepared in an aqueous base, and their effectson preventing skin irritation induced by alcohol was evaluated in avolunteer. In these studies, the anti-irritant composition was preparedin a clear formulation composition containing only soluble zinc saltsand panthenol. An anti-irritant zinc/panthenol composition (“zincpanthenol 1”) was prepared with the following composition:

Zinc gluconate 2.0% Zinc lactate 2.0% Panthenol 50W 10.0% Water 86.0%

Using this zinc/panthenol solution, the following alcohol splashformulations were prepared for testing:

Ingredients % Formulation A Zinc Panthenol 1 10 Alcohol SD 40 30Glycerin 1.0 Glucam P 20 1.0 Water 58 Formulation B Alcohol SD 40 30Glycerin 1.0 Glucam P 20 1.0 Panthenol 50W 10.0 Water 68.0 Formulation CZinc gluconate 0.2 Zinc lactate 0.2 Alcohol SD 40 30 Glycerin 1.0 GlucamP 20 1.0 Water 67.6Formulations A, B and C were tested in a volunteer, who applied 0.5 g ofthe control splash to one side of the face and the same amount of thetest splash to the other side of the face immediately after shaving. Theother two splashes were tested similarly on each of the next twoconsecutive days.

The results of these studies are shown in Table 19. Scoring of theresponse was performed as described immediately above for theantiperspirant and aftershave studies reported in Tables 17 and 18,respectively.

TABLE 19 Aqueous formulations containing zinc salts and panthenolprevented the stinging and irritation associated with alcohol-basedaftershave lotions. Irritation Stinging Splash A 0 0 Splash B 1+ 1+Splash C 0.5+ 1+

The following zinc/panthenol anti-irritant compositions also wereprepared:

(1) Alcohol-based Anti-irritant Cream for use Under Latex Glove

Ingredients Percent Water 23.57 Zinc acetate 0.1 Zinc lactate 0.1 Zincgluconate 0.3 Methocell K4MS 0.3 UcareJR 30 0.3 Glycerin 1.0 Panthenol50W 1.0 Alcohol.SDA-3C 67.6 Cromollient DP3A 2.0 Incroquat BA 85 0.5Phenoxy ethanol 0.7 Incroquat TMS Behenyl 0.7 Polowax A-31 0.3 PHMB 0.15(2) Alcohol-based Anti-irritant Surgical Prep

Ingredients Percent Water 22.27 Zinc lactate 0.2 Zinc gluconate 0.2Methocell K4MS 0.1 UcareJR 30 0.2 Panthenol 50W 1.0 Alcohol.SDA-40B 72.7CrodamolSTS 1.0 Incroquat BA 85 0.3 Procetyl 10 0.5 PHMB 0.15 Farnesol0.3 BZT 0.18 Propylene Glycol 1.0(3)Health Care Hand Disinfectant

Ingredients Percent Water 22.27 Zinc lactate 0.2 Zinc gluconate 0.2Methocell K4MS 0.1 UcareJR 30 0.2 Panthenol 50W 1.0 Alcohol.SDA-40B 72.7CrodamolSTS 1.0 Incroquat BA 85 0.3 Procetyl 10 0.5 PHMB 0.15 Farnesol0.3 BZT 0.18 Propylene Glycol 1.0(4) Anti-irritant Skin Lotion

Ingredients Percent Water 83.75 Zinc lactate 0.1 Zinc gluconate 0.3 Zincacetate 0.1 Polyox WSR 205 0.1 Kytamer 0.15 UcareJR 30 0.1 Panthenol 50W1.0 Germal+ 0.2 Petroleum Jelly 1.0 Crodamol GTCC 2.0 Incroquat TMSBehenyl 3.5 Polowax NF 3.0 Gycerin 2.0 Crodacol S95 1.0 Zinc stearate0.5 Zinc oxide 0.5 Farnesol 0.3 Lemon oil 0.3

The present invention further provides for an anti irritant zinccomposition for application on the surface of latex gloves. To reducelatex glove-related contact dermatitis, gloves can be coated with thefollowing anti irritant zinc slurry:

Ingredients % wt/wt Zinc gluconate  1–.5  Zinc lactate  1–.5  D,LPanthenol (50 W) 5–40 Glycerine 20–50  Zinc oxide 2–10 Zinc stearate2–10

10-20% of this Zinc slurry can be incorporated into the Silicone orpolyurethane fluid used as lubricant on the surface of the glove

5.15. Example 15 Antimicrobial Compositions Containing SynergisticCombinations of Emollient Solvents and Essential Oils and/orConstituents Thereof and/or Anti-inflammatory Agents

Antimicrobial agents such as biguanides, quaternary ammonium compoundsand the like are presently used as preservative/antimicrobial agents inskin-care formulations. However, these agents are potentially irritatingto certain individuals. Some of these antimicrobial agents can alsocause resistance in microorganisms when used over an extended period oftime.

Emollient solvents (ES) such as octoxyglycerine (Sensiva®), pentyleneglycol (Hydrolite-5), 1,2-hexanediol and caprylyl glycol (thesynergistic mixture called Symdiol-68) have been known to exhibitantimicrobial activity, especially against gram-positive organisms andthese have been used in combination with certain deodorizing actives toobtain efficient deodorizing compositions. See U.S. Pat. No. 5,516,510.These compounds also provide excellent emolliency when used in topicalformulations. Previous studies have shown that emollient solvents suchas Sensiva® produce a synergistic antimicrobial effect when used incombination with other previously-known antimicrobial agents. See U.S.patent Publication US2003/0152644.

Essential oils are volatile oils obtained from plant or animal sourcesand are composed of complex mixtures of several active agents, such asmonoterpene and sesquiterpene hydrocarbons, monoterpene andsesquiterpene alcohols, esters, ethers, aldehydes, ketones, oxides, andthe like. These essential oils (EO) and their active agents (orindividual constituents, “ICs”), either isolated from essential oils orchemically synthesized, have been mainly used as fragrance and flavoragents in several formulations. These EOs and ICs have also been knownto show antimicrobial, anti-inflammatory and wound-healing properties.

In order to develop a disinfectant composition that does not containantimicrobials, the efficacy of various combinations of ES and EO/IC wasevaluated to determine whether they would exhibit synergistic activityand broad spectrum antimicrobial activity. The effects of the additionof anti-inflammatory agents (AI) such as salicylic acid and theirderivatives-zinc salicylate and acetyl salicylic acid (aspirin) on theantimicrobial effects of the disinfectant composition were alsoevaluated.

In these studies, an alcoholic gel base was prepared and these ES andthe EOs and/or ICs and/or AIs were incorporated. The rapid antimicrobialactivity of these preparations was then assessed to determine whetherthey exhibited synergistic antimicrobial activity. Surprisingly, it wasdiscovered that ES and EO/IC exhibit synergistic rapid antimicrobialactivity against both-gram positive and gram-negative bacteria.Similarly, the ES and EO/IC also exhibit synergistic rapid antimicrobialactivity with AIs. Alcohol-based gels containing synergisticcombinations of the ES and IC and/or AI were then formulated and theirantimicrobial activity was evaluated and compared with the gelscontaining antimicrobials in the pig skin model (PSM). In addition,various topical alcohol-based antimicrobial formulations containing ESand EOs and/or ICs and/or AIs were developed.

In these studies, an alcohol-based gel was prepared as follows:

Alcohol Gel Base - 1 Ingredient % by weight UCare JR 400 0.1 MethodK100M 0.1 Water 40.0 Germall Plus 0.3 Ethanol 55.0 Ispropanol 2.0Incroquat Bethenyl TMS 0.7 Polawax A31 0.3 Glycerin 1.0 PPG-10 Cetylether (Procetyl-10) 0.5

The ES, EOs and/or ICs and/or AIs were incorporated in the Gel Base-1and the rapid antimicrobial activity of the resultant gel was evaluatedagainst S. aureus and E. coli. To determine the efficacy of theantimicrobial composition on the skin, which may be contaminated withblood or other proteinaceous fluids containing bacteria, the rapidactivity was evaluated in presence of serum using the following method.

0.5 ml of 10⁸ CFU/ml of S. aureus (or E. coli) was added to 0.5 ml ofbovine adult serum in a sterile culture tube and mixed. 0.5 ml of theformulation was added to the tube and vortexed for 15 seconds. Thismixture then was further diluted 1:100 with drug inactivating media(LTSB) and 0.5 ml of the diluted mixture was plated on a TSA plate. Theplates were incubated at 37° C. for 24 hours and the colony count per mlof culture was determined. The Gel Base-1 was taken as the control. Theresults of these studies are shown in Tables 20-23.

Table 20: Synergistic Activity of EOs or ICs against E. coli inAlcohol-based Gels

Test organism: E. coli

TABLE 20 Synergistic activity of EOs or ICs against E. coli inalcohol-based gels Test organism: E. coli log₁₀ Groups cfu/ml reductionGel Base (Control) 6.2 × 10⁷ — F (0.5) 1.0 × 10⁶ 1.8 LO (0.5) 2.6 × 10⁶1.3 PXE (0.5) 1.6 × 10⁶ 1.5 SEN (0.25) 8.0 × 10⁵ 1.9 SYM (1.0) 4.6 × 10⁶1.1 SEN (0.25) + LO (0.5)  2.0 × 10²: 5.5 SEN (0.25) + F (0.5) 4.0 × 10³4.2 SEN (0.25) + PXE (0.5) 1.9 × 10³ 4.5 SYM (1.0) + F (0.5) 3.2 × 10³4.3 SEN (0.25) + F (0.5) + SYM (1.0) 1.3 × 10² 5.7 SEN (0.25) + F(0.5) + PXE (0.5) 1.9 × 10³ 4.5 Notes: Figures in brackets are theconcentration of the ingredients (% w/w) that were added to Alcohol GelBase-1. F: Farnesol; LO: Lavender oil; PXE: Phenoxyethanol; SEN:Sensiva ®; and SYM: Symdiol-68.

The results shown in Table 20 demonstrate that Sensiva® (an ES) actssynergistically with an EO (lavender oil) to produce a 5.5-log₁₀reduction in colony formation. Sensiva® also acts synergistically withan IC (farnesol, an active agent of the essential oils derived fromlemongrass, tuberose and petitgrain), to produce a 4.2-log₁₀ reductionin colony formation. Furthermore, Sensiva® acts synergistically withphenoxyethanol, a constituent of sage oil, to produce a 4.5-log₁₀reduction in colony formation. Similarly, symdiol (an ES) and farnesol(an IC) show good synergistic action against E. Coli (a 4.3-log₁₀reduction in colony formation).

The antimicrobial activity of the Sensiva®-farnesol combination can befurther enhanced if symdiol (an ES) is added along with theseingredients (a 5.7-log₁₀ reduction). Hence, a synergistic combination ofES and EO or ICs can be used to obtain rapid antimicrobial activityagainst gram-negative microorganisms as E. coli.

TABLE 21 Synergistic activity of ES and EOs or ICs against S. aureus inalcohol-based gels Test organism: S. aureus log₁₀ Groups cfu/mlreduction Gel Base (Control) 5.0 × 10⁷ — F (0.5) 3.3 × 10⁶ 1.2 F (1.0)3.3 × 10⁶ 1.2 PXE (0.5) 7.9 × 10⁵ 1.8 LO (1.0) 3.5 × 10⁶ 1.1 SYM (1.0)3.2 × 10⁶ 1.2 SEN (1.0) 2.5 × 10⁶ 1.3 SEN (2.0) 1.6 × 10⁴ 3.5 LO (1.0) +SEN (1.0) 2.3 × 10⁴ 3.3 LO (1.0) + SYM (1.0) 2.4 × 10⁶ 1.3 F (1.0) + SEN(1.0) 9.1 × 10⁴ 2.7 PXE (0.5) + SEN (2.0) 1.2 × 10⁴ 3.6 F (0.5) + SEN(2.0) 2.4 × 10⁴ 3.6 LO (1.0) + SEN (1.0) + SYM (1.0) 2.6 × 10³ 4.3 PXE(0.5) + SEN (2.0) + F (0.5) 3.2 × 10³ 4.2 Notes: Figures in brackets arethe concentration of the ingredients (% w/w) that were added to AlcoholGel Base-1. F: Farnesol; LO: Lavender oil; PXE: Phenoxyethanol; SEN:Sensiva ®; and SYM: Symdiol-68.

The results shown in Table 21 demonstrate that the combination oflavender oil (an EO) and Sensiva® (an ES) show synergistic rapidantimicrobial action against S. aureus (a 3.3-log₁₀ reduction ingrowth). Symdiol-68 (another ES) does not show synergism with lavenderoil, but does potentiate the synergistic activity of the lavenderoil-Sensiva(V combination (a 4.3-log₁₀ reduction). Sensiva® also showssynergy with farnesol (an IC) in its antimicrobial action against S.aureus, but to a somewhat lesser degree (a 2.7-log₁₀ reduction).Sensiva® did not show any synergistic activity with PXE against thisorganism. Thus, an ES (Sensiva®) acts synergistically with an EO(lavender oil) in its antimicrobial action against the gram-positive S.aureus, and addition of another ES (Symdiol-68) further enhances theactivity of the synergistic combination.

Lavender oil has a strong fragrance and therefore its use may not bedesirable in certain formulations. Since farnesol also shows synergisticactivity with Sensiva®, the antimicrobial activity of the combination ofSensiva®, farnesol and PXE was determined against S. aureus, and wasfound to be comparable (a 4.2-log₁₀ reduction in bacterial growth to thecombination of Sensiva®®, lavender oil and Symdiol. The combination ofSensiva®, farnesol and PXE therefore can be used to give comparableantimicrobial activity against S. aureus as the combination of Sensiva®,lavender oil, and symdiol in formulations where the odor of lavender oilis undesirable.

TABLE 22 Synergistic activity of AIs (aspirin or zinc salicylate) withES against E. coli in alcohol-based gels Test organism: S. aureus log₁₀Groups cfu/ml reduction Gel Base (Control) 4.9 × 10⁷ — ASP (2)   7 × 310⁵ 1.8 SEN (0.2) 9.0 × 10⁵ 1.8 PXE (0.5) 1.6 × 10⁶ 1.5 SEN (0.2) + ASP(2) 2.3 × 10³ 4.3 SEN (0.2) + ZS (2) 6.7 × 10¹ 5.8 SEN (0.5) + ASP (2) +PXE (0.5) 6.7 × 10¹ 5.8 SEN (0.2) + ZS (2) + PXE (0.5) 6.7 × 10¹ 5.8Notes: Figures in brackets are the concentration of the ingredients (%w/w) that were added to Alcohol Gel Base-1. ASP: Acetyl salicylic acid(aspirin); PXE: phenoxyethanol; SEN: Sensiva ®; ZS: zinc salicylate.

The results presented in Table 22 demonstrate that the AIs aspirin andzinc salicylate show synergism with Sensiva® (an ES) in itsantimicrobial activity against E. coli. The addition of PXE (an IC)further potentiates the antimicrobial activity. Salicylic acid alsoshows synergy with both Sensiva® (an ES) and PXE (and ES) in itsantimicrobial activity against S. aureus (Table 23).

TABLE 23 Synergistic activity of AI (salicyclic acid) with ES and ICagainst S. aureus in alcohol-based gels Test organism: S. aureus log₁₀Groups cfu/ml reduction Gel Base (Control) 4.7 × 10⁷ — SA (2) 1.9 × 10⁵2.4 SEN (1) 2.7 × 10⁵ 2.2 PXE (1) 1.8 × 10⁶ 1.4 SEN (1) + SA (2) 6.7 ×10¹ 5.8 PXE (1) + SA (2) 9.3 × 10² 4.7 SEN (1) + PXE (1) 1.0 × 10⁵ 2.7SEN (1) PXE (1) + SA (2) 6.7 × 10¹ 5.8 Notes: Figures in brackets arethe concentration of the ingredients (% w/w) that were added to AlcoholGel Base-1. SA: salicylic acid; PXE: phenoxyethanol; SEN: Sensiva ®.

The results presented in Tables 20 and 21 demonstrated that ESs and EOsor ICs show synergistic activity against both gram-negative andgram-positive microorganisms. These reagents, therefore, were chosen forincorporation into an alcohol-based gel for further study of theantimicrobial efficacy using the Pig Skin Model (PSM) developed in ourlaboratory. In these studies, the activities of these gels wereevaluated and compared to alcohol-based gels having a similarcomposition but containing more traditional antimicrobials such asbiguanides or quaternary ammonium compounds. Alcohol-based disinfectantgels containing synergistic combinations of ES and IC, or ES, IC, and AIwere also tested.

For these studies, an alcohol gel-base (Alcohol Gel Base-2) having thefollowing composition was prepared:

Alcohol Gel Base - 2 Ingredient % by weight UCare JR 30M 0.2 Method4-100 0.2 Water 35.15 German Plus 0.15 Ethanol 62.0 Silicone (DowCorning 245 fluid) 0.5 Incroquat Bethenyl TMS 0.35 Polawax A31 0.15Polawax A31 0.15 Incroquat BA 85 0.3 PPG-10 Cetylether (Procetyl-10) 0.5Panthenol 0.5The ES, EO/IC and/or the AI then were incorporated into the Alcohol GelBase-2 and the antimicrobial efficacy of the resultant formulation wasevaluated in the Pig Skin Model (PSM) using the procedure describedbelow.

The skin of freshly killed pig was obtained from a slaughterhouse,washed with water, dehaired, and defatted using scalpel. It was then cutinto smaller sections, rinsed with water, and preserved in sealedplastic bags in a freezer. Before use, a section was removed, thawed,rinsed in water, and cut into pieces (3'3 cm) with a blade. These skinpieces were mounted on holders (plastic plates of 5 cm diameter) withepoxy to expose the skin surface. For each test, two pieces were used.One of the two pieces of pig skin was contaminated with 100μ S.epidermidis (10⁸ cfu/ml) and the two pieces were rubbed against eachother for 15 sec. These pieces were then incubated at 37° C. for 3hours. After the end of this period, the pieces were removed from theincubator and 0.1 ml of saline (0.9%) was applied on each skin piece andspread evenly on the skin with a glass rod. 50μ of the formulation gelwas applied on each piece of the pig skin and the two skins were rubbedagainst each other for 15 sec. The two skin pieces were then left to dryfor 1 minute. 0.1 ml of Triton X100 solution was applied to each of thepig skins and the two skins again were rubbed together for 15 sec. Eachskin was rinsed with 4.9 ml of Triton X100 solution and the washings ofeach skin were separately collected in a Petri dish. The Triton-rinsecollected from each of the pig skin pieces was then suitably dilutedwith Triton X100 solution and an aliquot was plated on D/E agar todetermine microbial count. As a control, the skin was treated in asimilar way except that PBS was used instead of test formulations. Theresults of these studies are shown in Tables 24 and 25.

TABLE 24 Antimicrobial activity of alcohol-based gel disinfectantscontaining ES and IC in a pig skin model Test organism: S. epidermidisMicrobial count log¹⁰ Formulation Groups (cfu/ml) reduction ControlPhosphate Buffered Saline (PBS) 3.2 × 10⁶ — Gel A SEN (1.0) + F (0.5) +PXE (0.5) 9.3 10² 3.5 Gel B BZT (0.18) + F (0.5) 1.5 × 10⁴ 2.3 Gel CPHMB (0.15) + F (0.5) 1.3 × 10³ 3.4 Notes: Figures in brackets are theconcentration of the ingredients (% w/w) that were added to Alcohol GelBase-2. SEN: Sensiva ®; PXE: phenoxyethanol; BZT; benzethonium chloride;F: farnesol; PHMB: a biguanide.

The Gel A formulation is able to produce 3.5-log₁₀ reduction inmicrobial growth in the pig skin model (Table 24). Gel A does notcontain any of the “traditional” antimicrobial agents such as biguanidesor quaternary ammonium compounds; thus, the antimicrobial efficacy ofGel A is solely attributable to a synergistic combination of ES and ICscontained in this gel. The antimicrobial activity of Gel A is comparableto that of Gel C (a 3.4-log₁₀ reduction in colony formation), whichcontains a biguanide (PHMB) along with the IC (farnesol), and is betterthan that of Gel B (a 2.3-log₁₀ reduction in growth), which contains aquaternary ammonium compound (benzethonium chloride) along with the IC(farnesol). Hence, a combination of ES and IC can be used to conferantimicrobial properties to an alcohol-based gel formulation.

TABLE 25 Antimicrobial activity of alcohol-based gel disinfectantscontaining ES and IC in a pig skin model Test organism: S. epidermidisMicrobial count log¹⁰ Formulation Groups (cfu/ml) reduction ControlPhosphate Buffered Saline (PBS) 4.2 × 10⁶ — Gel D SEN (1) + PXE (0.5)6.6 × 10⁴ 1.8 Gel E SEN (1) + PXE (0.5) + SA (1) 8.8 × 10³ 2.7 Gel F SEN(1) + PXE (0.5) + F (0.3) 1.1 × 10⁴ 2.6 Gel G SEN (1) + PXE (0.5) + F(0.3) + 4.6 × 10³ 3.0 SA (1) Notes: Figures in brackets are theconcentration of the ingredients (% w/w) that were added to Alcohol GelBase-2. SEN: Sensiva ®; PXE: phenoxyethanol; SA: salicylic acid; F:farnesol.

Salicylic acid (an AI) enhances the activity of the ES/IC combination ofSensiva® and PXE from a 1.8- to a 2.7-log₁₀ reduction in microbialgrowth (Table 25). Thus, a combination of ES, IC and AI also can be usedto confer antimicrobial activity to an alcohol-based gel formulation.

Pig skin has been shown to have similar composition and behavior as thatof human skin, and has been used in evaluating antimicrobial efficacy ofskin disinfectants. See Bush L W, Benson L M, White J H. Pig skin astest substrate for evaluating topical antimicrobial activity. J ClinMicrobiol 1986;24:343-48; Bissett D L, McBride J F. The use of thedomestic pig as an animal model for human dry skin and for comparison ofdry and normal skin properties. J. Soc Cosmet Chem 1983;34:317-26; MeyerW, Schwarz R, Neurand K. The skin of domestic pig. Curr. Problem Dematol1978,7:39-52. Thus it is anticipated that the same formulations can beused as hand-disinfectants for human-use.

Examples of disinfectant formulations containing ES and/or EO/IC and/orAI include the following:

Example 15-1

UCare JR 30M 0.2 Methocel 40-100 0.2 Water 33.15 Germall Plus 0.15Ethanol 62.0 Silicone (Dow Corning 245 fluid) 0.5 Incroquat Behenyl TMS0.35 Polawax A31 0.15 Incroquat BA 85 0.3 PPG-IO Cetyl ether(Procetyl-10) 0.5 Panthenol 0.5 Sensiva ® 1.0 Farnesol 0.5Phenoxyethanol 0.5

Example 15-2

UCare JR 30M 0.2 Methocel 40-100 0.2 Water 33.35 Germall Plus 0.15Ethanol 62.0 Silicone (Dow Corning 245 fluid) 0.5 Incroquat Behenyl TMS0.35 Polawax A31 0.15 Incroquat BA 85 0.3 PPG-IO Cetyl ether(Procetyl-10) 0.5 Panthenol 0.5 Sensiva ® 1.0 Farnesol 0.5Phenoxyethanol 0.5

Example 15-3

UCare JR 30M 0.2 Methocel 40-100 0.2 Water 32.35 Germall Plus 0.15Ethanol 62.0 Silicone (Dow Corning 245 fluid) 0.5 Incroquat Behenyl TMS0.35 Polawax A31 0.15 Incroquat BA 85 0.3 PPG-IO Cetyl ether(Procetyl-10) 0.5 Panthenol 0.5 Sensiva ® 1.0 Farnesol 0.3Phenoxyethanol 0.5 Salicylic acid 1.0

Various publications and have been referenced herein, the contents ofwhich are hereby incorporated by reference in their entireties.

1. A topical composition comprising two or more water-soluble, organicsalts of zinc at concentrations between 0.1% and 2% (w/w), wherein thewater-soluble, organic salts of zinc are selected from the groupconsisting of zinc acetate, zinc butyrate, zinc citrate, zinc gluconate,zinc glycerate, zinc glycolate, zinc formate, zinc lactate, zincpicolinate, zinc proprionate, zinc tartrate and zinc undecylenate,between 0.2% and 5% panthenol, between 0.2% and 3% (w/w) octoxyglycerin,and between 1.0% and 4% salicylic acid, wherein the amounts ofoctoxyglycerin and salicylic acid exhibit a synergistic antimicrobialactivity.
 2. The topical composition of claim 1, wherein the zinc saltsare present in an amount effective in reducing or preventing irritation.3. The topical composition of claim 1, further comprising an essentialoil or active component thereof.
 4. A topical composition comprising twoor more water-soluble, organic salts of zinc at concentrations between0.1% and 2% (w/w), wherein the water-soluble, organic salts of zinc areselected from the group consisting of zinc acetate, zinc butyrate, zinccitrate, zinc gluconate, zinc glycerate, zinc glycolate, zinc formate,zinc lactate, zinc picolinate, zinc proprionate, zinc tartrate and zincundecylenate, salicylic acid and between 0.2% and 5% panthenol.